Diphtheria antitoxin levels in the Netherlands: a population-based study.In a population-based study in the Netherlands, diphtheria antitoxin diphtheria antitoxin n. The antitoxin specific for the toxin produced by Corynebacterium diphtheriae. antibodies were measured with a toxin-binding inhibition assay in 9,134 sera from the general population and religious communities refusing vaccination vaccination, means of producing immunity against pathogens, such as viruses and bacteria, by the introduction of live, killed, or altered antigens that stimulate the body to produce antibodies against more dangerous forms. . The Dutch immunization immunization: see immunity; vaccination. program appears to induce long-term protection against diphtheria diphtheria (dĭfthēr`ēə), acute contagious disease caused by Corynebacterium diphtheriae (Klebs-Loffler bacillus) bacteria that have been infected by a bacteriophage. It begins as a soreness of the throat with fever. . However, a substantial number of adults born before the program was introduced had no protective diphtheria antibody levels. Although herd immunity herd immunity n. 1. Resistance to the spread of infectious disease in a group because susceptible members are few, making transmission from an infected member unlikely. 2. seems adequate, long-term population protection cannot be assured. As more than 60% of orthodox reformed persons have antibody levels lower than 0.01 IU/ml, introduction of diphtheria into religious communities refusing vaccination may constitute a danger of spread of the bacterium bacterium /bac·te·ri·um/ (bak-ter´e-um) pl. bacte´ria [L.] in general, any of the unicellular prokaryotic microorganisms that commonly multiply by cell division, lack a nucleus or membrane-bound organelles, and possess a cell . The recent diphtheria epidemics in eastern Europe Eastern Europe The countries of eastern Europe, especially those that were allied with the USSR in the Warsaw Pact, which was established in 1955 and dissolved in 1991. are a warning that diphtheria can make a comeback in susceptible populations (1). The World Health Organization (WHO) recommends the assessment of diphtheria immunity in nonepidemic countries, to prevent any indigenous cases in the European region by the year 2000 (2). In the Netherlands, the Netherlands, The officially Kingdom of The Netherlands byname Holland Country, northwestern Europe. Area: 16,034 sq mi (41,528 sq km). Population (2005 est.): 16,300,000. Capital: Amsterdam. Seat of government: The Hague. Most of the people are Dutch. last diphtheria epidemic occurred during World War II (220,000 cases in 1940 to 1946). Diphtheria vaccination was introduced in 1952 for persons born after 1945. Under the current schedule, children are vaccinated at ages 3, 4, 5, and 11 months with diphtheria, tetanus tetanus (tĕt`nəs, –ənəs) or lockjaw, acute infectious disease of the central nervous system caused by the toxins of Clostridium tetani. , pertussis pertussis: see whooping cough. , and inactivated inactivated rendered inactive; the activity is destroyed. inactivated viruses treated so that they are no longer able to produce evidence of growth or damaging effect on tissue. polio vaccine Two polio vaccines are used throughout the world to combat polio. The first was developed by Jonas Salk, first tested in 1952, and announced to the world by Salk on April 12, 1955. It consists of an injected dose of inactivated (dead) poliovirus. (DTP-IPV) and at ages 4 and 9 years with DT-IPV. For the past 25 years, the Years, The the seven decades of Eleanor Pargiter’s life. [Br. Lit.: Benét, 1109] See : Time vaccine coverage for at least three vaccinations at the age of 12 months has been 97%. Rare exposure to Corynebacterium diphtheriae Corynebacterium diph·the·ri·ae n. Klebs-Loeffler bacillus. Corynebacterium diphtheriae The causative agent of diphtheria, which produces a potent exotoxin Reservoir Humans Epidemiology Airborne, infected fomites, may have led to lack of boosting opportunities (1). As in other industrialized in·dus·tri·al·ize v. in·dus·tri·al·ized, in·dus·tri·al·iz·ing, in·dus·tri·al·iz·es v.tr. 1. To develop industry in (a country or society, for example). 2. countries, lack of immunity in older persons is a reason for concern (3,4). Furthermore, in the Netherlands, the immune status of sociogeographically clustered members of religious communities who refuse vaccination may be even more unfavorable. Inadequate herd immunity to diphtheria in these groups could lead to outbreaks similar to the poliomyelitis poliomyelitis (pō'lēōmī'əlī`tĭs), polio, or infantile paralysis, acute viral infection, mainly of children but also affecting older persons. outbreaks in the Netherlands (5). A large population-based serum bank allowed us to assess the diphtheria immunity in the general Dutch population and in persons refusing vaccination (6). The Study From October 1995 through December 1996, a population-based serum bank with specimens from 9,948 persons was established (6). Our objective was to select 40 municipalities with samples proportional to population size. In each of five regions, eight municipalities were included. For each of these 40 municipalities, an age-stratified sample of 380 persons was drawn from the population register (7). Participants were requested to have a blood sample drawn, complete a questionnaire, and provide immunization and military service records. Participants were also selected from eight additional municipalities with low vaccine coverage to assess the immunity of members of religious communities that refuse vaccination. The nationwide sample had 8,357 (55%) participants, and the low vaccine coverage sample had 1,589 (52.5%). Sufficient serum was available for testing 7,715 of the nationwide participants and 1,419 of the participants in the sample with low vaccine coverage. Methods Sera were stored at -86 [degrees] C. The level of diphtheria antitoxin antibodies was measured with a toxin-binding inhibition assay (8). In brief, twofold serum dilution series were incubated with a fixed amount of toxin toxin, poison produced by living organisms. Toxins are classified as either exotoxins or endotoxins. Exotoxins are a diverse group of soluble proteins released into the surrounding tissue by living bacterial cells. , and the nonneutralized toxin was measured in an enzyme-linked immunosorbent assay enzyme-linked immunosorbent assay n. ELISA. Enzyme-linked immunosorbent assay (ELISA) A diagnostic blood test used to screen patients for AIDS or other viruses. (ELISA ELISA (e-li´sah) Enzyme-Linked Immuno-Sorbent Assay; any enzyme immunoassay using an enzyme-labeled immunoreactant and an immunosorbent. ELISA n. ) with equine equine Any member of the ungulate family Equidae, which includes the modern horses, zebras, and asses, all in the genus Equus, as well as more than 60 species known only from fossils. Equines descended from the dawn horse (see Eohippus). antitoxin antitoxin, any of a group of antibodies formed in the body as a response to the introduction of poisonous products, or toxins. By introducing small amounts of a specific toxin into the healthy body, it is possible to stimulate the production of antitoxin so that the purified from hyperimmune hyperimmune /hy·per·im·mune/ (hi?per-i-mun´) possessing very large quantities of specific antibodies in the serum. hyperimmune possessing very large quantities of specific antibodies in the serum. serum as coat and peroxidase-labeled horse antidiphtheria IgG as conjugate conjugate /con·ju·gate/ (kon´jdbobr-gat) 1. paired, or equally coupled; working in unison. 2. a conjugate diameter of the pelvic inlet; used alone usually to denote the true conjugate diameter; see . International units international units, n.pl a unit of measurement that evaluates the potency of a substance. Because it measures potency instead of quantity, there is a different international unit-to-mg conversion ratio for each particular substance. were calculated according to according to prep. 1. As stated or indicated by; on the authority of: according to historians. 2. In keeping with: according to instructions. 3. the WHO reference standard serum (10 IU/ml) by the four-parameter fit method in Kineticalc (KC4, Biolyse) with a Bio-Tek plate reader (EL312d). The minimum level of detection was 0.01 IU/ml, and samples below this level were set to 0.005 IU/ml for calculating geometric mean (mathematics) geometric mean - The Nth root of the product of N numbers. If each number in a list of numbers was replaced with their geometric mean, then multiplying them all together would still give the same result. titers. The correlation of this method with the Vero neutralization neutralization, chemical reaction, according to the Arrhenius theory of acids and bases, in which a water solution of acid is mixed with a water solution of base to form a salt and water; this reaction is complete only if the resulting solution has neither acidic nor assay has been confirmed recently (r [is greater than or equal to] 0.95) (9). Antitoxin antibody levels were classified according to international standards as [is less than] 0.01 IU/ml (no protection), 0.01 IU/ml to 0.1 IU/ml (basic protection) and [is greater than] 0.1 IU/ml (full protection) (10). Analysis Frequencies and geometric mean titers in each municipality MUNICIPALITY. The body of officers, taken collectively, belonging to a city, who are appointed to manage its affairs and defend its interests. were weighted by the proportion of the age group in the population. To produce national estimates, the weighted frequencies and geometric mean titers were averaged over the 40 municipalities (7). For the low vaccine coverage sample, they were averaged by weighting the population of the municipality. Data on age, sex, marital status marital status, n the legal standing of a person in regard to his or her marriage state. , country of nationality, degree of urbanization, region, and contact information for all participants and nonparticipants were available. The effect of differential probabilities of response for these variables on both sample estimates was less than one standard error and was therefore disregarded. Linear regression Linear regression A statistical technique for fitting a straight line to a set of data points. analysis was used to study the persistence of diphtheria antitoxin antibodies after full immunization in the national immunization program. The association between diphtheria antibody titer antibody titer The amount of a specific antibody present in the serum, usually as a result of an acquired infection; titers for IgM usually rise abruptly at the time of infection–acute phase and fall slowly; during the 'convalescent' phase, IgG ↑ and is ([sup.2]log) and age in [sup.2]log years was studied for persons who received the sixth documented vaccination at 8 to 9 years of age, without self-reported or documented revaccination re·vac·ci·na·tion n. Vaccination of a person previously vaccinated. or history of military service. Age-Specific Immunity Levels to Diphtheria Antitoxin In the nationwide sample, 58.1%, 30.0%, and 11.9% of persons [is less than or equal to] 79 years of age had full, basic, or no diphtheria protection, respectively (Table 1). Women had lower levels of full protection and geometric mean titers. A greater percentage of persons from the municipalities with low vaccine coverage and of members of religious communities in the low vaccine coverage sample had no protection (Table 2). When members of the religious community were excluded from this low vaccine coverage sample, the percentages of full, basic, and no protection were 57.3%, 25.2%, and 17.5%, respectively (Table 2). Table 1. Diphtheria immunity in a nationwide sample of persons [is less than or equal to] 79 years of age, the Netherlands
<0.01 0.01-0.1
Sample No. IU/ml (95% CI(a)) IU/ml
Overall 7,715 11.9 (10.7-13.1) 30.0
Men 3,644 9.3 (8.0-10.6) 28.1
Women 4,071 14.4 (12.6-16.2) 31.6
[is greater than
or equal to] 0.1
Sample (95% CI) IU/ml (95% CI)
Overall (28.3-31.7) 58.1 (56.2-59.9)
Men (25.9-30.2) 62.6 (60.1-65.2)
Women (29.7-33.6) 54.0 (51.9-56.0)
Geometric
Sample mean titer (95% CI)
Overall 0.12 (0.11-0.13)
Men 0.14 (0.13-0.16)
Women 0.10 (0.09-0.11)
(a) CI, confidence interval confidence interval, n a statistical device used to determine the range within which an acceptable datum would fall. Confidence intervals are usually expressed in percentages, typically 95% or 99%. . Table 2. Diphtheria immunity in a sample of persons [is less than or equal to] 79 years of age with low vaccine coverage, the Netherlands
Nationwide <0.01 <0.01
sample(a) No. IU/ml (95% CI(b)) IU/ml
OR
Overall 233 60.9 (42.9-78.9) 12.4
Men 116 69.7 (54.2-85.2) 10.4
Women 117 52.3 (27.7-76.8) 15.0
NMCR
Overall 1,259 17.5 (15.5-19.4) 25.2
Men 590 11.5 (8.2-14.8) 25.5
Women 669 21.7 (18.0-25.4) 25.0
TLVC
Overall 1,492 24.3 (20.5-28.0) 23.6
Men 706 20.6 (16.6-24.7) 23.4
Women 786 26.7 (21.1-32.4) 23.3
[is greater than
Nationwide or equal to] 0.1
sample(a) (95% CI) IU/ml (95% CI)
OR
Overall (6.0-18.7) 26.7 (13.8-39.7)
Men (4.2-16.6) 19.9 (8.2-31.5)
Women (6.9-23.2) 32.7 (15.3-50.1)
NMCR
Overall (21.3-29.2) 57.3 (52.2-62.4)
Men (20.5-30.6) 63.0 (55.4-70.5)
Women (21.2-28.9) 53.3 (48.6-58.0)
TLVC
Overall (20.1-27.1) 52.1 (48.2-56.0)
Men (18.9-27.8) 56.0 (50.3-61.7)
Women (19.9-26.7) 50.0 (45.3-54.7)
Nationwide Geometric
sample(a) mean titer (95% CI)
OR
Overall 0.02 (0.01-0.04)
Men 0.01 (0.01-0.03)
Women 0.03 (0.01-0.06)
NMCR
Overall 0.10 (0.09-0.12)
Men 0.14 (0.13-0.16)
Women 0.08 (0.07-0.10)
TLVC
Overall 0.08 (0.07-0.09)
Men 0.10 (0.08-0.12)
Women 0.07 (0.06-0.09)
(a) OR, orthodox reformed; NMCR NMCR New Markets Credit (IRS deduction) NMCR Navy-Marine Corps Relief Society , Not member of religious communities; TLVC, total low vaccine coverage. (b) CI, confidence interval. For the ages of 1, 4, and 8 to 9 years, the geometric mean titer titer /ti·ter/ (ti´ter) the quantity of a substance required to react with or to correspond to a given amount of another substance. and percentages of persons with full protection increased (Table 3). The percentage with full protection decreased after the age of 10 to 14 years, but increased for the 35to 44-year age group (Figure 1). After the age of 40 to 44 years, the percentage with full protection and the geometric mean titer decreased. Although the geometric mean titers differed statistically significantly by gender only after the age of 30 years, they were slightly lower for females 5 to 9 years of age and older (Table 3). [Figure 1 ILLUSTRATION OMITTED] Table 3. Age-specific prevalence of diphtheria immunity and geometric mean titers for children [is less than or equal to] 14 years of age and for men and women [is less than or equal to] 79 years of age in a nationwide sample, the Netherlands Age group <0.01 0.01-0.1 (yrs) No. IU/ml (95% CI(a)) IU/ml (95% CI) <1 187 3.7 (1.1-6.4) 25.5 (18.6-32.4) 1 185 1.2 (0.0-3.0) 9.9 (5.4-14.3) 2 156 1.9 (0.1-3.7) 34.9 (24.2-45.5) 3 215 1.7 (0.1-3.3) 35.5 (27.7-43.3) 4 153 0.6 (0.0-1.7) 8.7 (3.7-13.7) 5 102 1.4 (0.0-3.3) 6.3 (1.9-10.7) 6 121 0.9 (0.0-2.6) 20.0 (11.7-28.3) 7 101 2.3 (0.0-5.4) 31.8 (20.3-43.3) 8 127 0.7 (0.0-2.0) 23.6 (14.9-32.3) 9 97 0.0 (0.0-0.0) 11.8 (3.2-20.4) 10 113 0.7 (0.0-2.1) 6.7 (1.9-11.5) 11 111 0.7 (0.0-1.9) 8.3 (3.5-13.2) 12 122 0.6 (0.0-1.9) 17.0 (9.2-24.8) 13 126 0.0 (0.0-0.0) 27.3 (18.0-36.7) 14 102 0.4 (0.0-1.1) 26.7 (14.0-39.3) Men <1 104 3.5 (0.04-7.0) 25.2 (15.8-34.6) 1-4 376 1.8 (0.5-3.1) 22.9 (17.0-28.8) 5-9 296 0.6 (0.0-1.4) 16.9 (12.4-21.4) 10-14 280 0.6 (0.0-1.7) 16.5 (11.7-21.3) 15-19 209 1.0 (0.0-2.4) 25.8 (19.7-31.9) 20-24 139 4.0 (0.4-7.6) 25.5 (17.8-33.2) 25-29 150 2.9 (0.0-6.2) 30.6 (21.7-39.5) 30-34 188 7.0 (1.6-12.4) 31.5 (23.0-40.0) 35-39 220 5.1 (1.3-8.9) 27.4 (20.7-34.1) 40-44 230 3.8 (1.1-6.5) 16.3 (11.0-21.6) 45-49 208 13.7 (7.8-19.6) 26.6 (21.4-31.8) 50-54 228 15.0 (10.4-19.6) 31.1 (24.7-37.5) 55-59 251 8.8 (4.0-13.6) 38.8 (32.1-45.5) 60-64 216 10.3 (6.2-14.4) 52.3 (43.8-60.8) 65-69 200 26.5 (19.6-33.4) 39.4 (30.4-48.4) 70-74 193 46.2 (36.9-55.5) 26.6 (19.2-34.0) 75-79 156 45.0 (35.8-54.2) 26.2 (17.8-34.6) Women <1 83 4.2 (0.0-8.9) 26.6 (13.7-39.5) 1-4 333 2.2 (0.5-3.9) 22.2 (16.7-27.7) 5-9 252 1.8 (0.0-3.7) 23.8 (16.2-31.4) 10-14 294 0.3 (0.0-0.8) 18.6 (12.9-24.3) 15-19 243 0.7 (0.0-1.7) 28.2 (21.9-34.5) 20-24 199 2.8 (0.4-5.2) 31.3 (23.6-39.0) 25-29 226 5.0 (1.5-8.5) 27.1 (20.3-33.9) 30-34 244 10.0 (5.7-14.3) 36.9 (30.5-43.3) 35-39 282 5.6 (2.5-8.7) 37.0 (29.6-44.4) 40-44 247 8.7 (4.8-12.6) 24.4 (18.5-30.3) 45-49 261 22.0 (15.8-28.2) 37.6 (30.6-44.6) 50-54 264 28.2 (20.2-36.2) 41.7 (34.5-48.9) 55-59 250 22.3 (16.3-28.3) 49.7 (43.6-55.8) 60-64 237 29.2 (22.9-35.5) 45.9 (39.7-52.1) 65-69 263 38.0 (30.6-45.4) 34.3 (29.0-39.6) 70-74 218 58.2 (50.8-65.6) 25.0 (18.9-31.1) 75-79 175 52.7 (43.8-61.6) 26.6 (19.4-33.8) Age [is greater than Geometric group or equal to] 0.1 mean (yrs) IU/ml (95% CI) titer (95% CI) <1 70.7 (63.4-78.1) 0.19 (0.15-0.24) 1 88.9 (84.3-93.5) 0.57 (0.45-0.72) 2 63.3 (52.9-73.6) 0.15 (0.12-0.19) 3 62.8 (54.7-70.9) 0.16 (0.12-0.22) 4 90.7 (85.7-95.7) 0.81 (0.60-1.10) 5 92.3 (87.7-97.0) 0.43 (0.35-0.52) 6 79.1 (70.9-87.4) 0.26 (0.21-0.34) 7 65.9 (54.7-77.2) 0.16 (0.13-0.20) 8 75.8 (66.9-84.6) 0.28 (0.20-0.38) 9 88.2 (79.6-96.8) 0.71 (0.51-0.99) 10 92.6 (87.7-97.5) 0.54 (0.42-0.69) 11 91.0 (85.8-96.2) 0.36 (0.30-0.44) 12 82.4 (74.2-90.5) 0.28 (0.22-0.35) 13 72.7 (63.3-82.0) 0.23 (0.18-0.29) 14 72.9 (60.3-85.6) 0.22 (0.15-0.31) Men <1 71.3 (61.4-81.2) 0.18 (0.13-0.24) 1-4 75.3 (69.1-81.5) 0.31 (0.25-0.38) 5-9 82.5 (77.9-87.1) 0.34 (0.28-0.40) 10-14 83.0 (78.0-88.0) 0.32 (0.27-0.38) 15-19 73.1 (67.1-79.1) 0.19 (0.16-0.23) 20-24 70.5 (62.0-79.0) 0.15 (0.12-0.19) 25-29 66.5 (56.9-76.1) 0.18 (0.14-0.24) 30-34 61.5 (52.1-70.9) 0.14 (0.10-0.19) 35-39 67.5 (60.8-74.2) 0.18 (0.14-0.23) 40-44 79.9 (73.9-85.9) 0.25 (0.20-0.31) 45-49 59.7 (51.8-67.6) 0.13 (0.09-0.18) 50-54 53.9 (46.5-61.3) 0.10 (0.08-0.13) 55-59 52.4 (46.0-58.8) 0.10 (0.08-0.12) 60-64 37.4 (29.9-44.9) 0.07 (0.06-0.09) 65-69 34.1 (26.2-42.0) 0.05 (0.04-0.06) 70-74 27.1 (19.2-35.2) 0.03 (0.02-0.04) 75-79 28.8 (20.8-36.8) 0.03 (0.02-0.04) Women <1 69.3 (56.7-81.9) 0.19 (0.13-0.27) 1-4 75.6 (70.0-81.2) 0.30 (0.25-0.37) 5-9 74.5 (68.2-80.8) 0.29 (0.24-0.36) 10-14 81.1 (75.4-86.8) 0.29 (0.24-0.33) 15-19 71.1 (64.8-77.4) 0.17 (0.15-0.20) 20-24 65.9 (58.3-73.5) 0.14 (0.12-0.18) 25-29 67.9 (60.5-75.3) 0.14 (0.11-0.18) 30-34 53.0 (47.3-58.7) 0.11 (0.09-0.13) 35-39 57.4 (50.6-64.2) 0.13 (0.11-0.15) 40-44 66.9 (60.9-72.9) 0.16 (0.12-0.20) 45-49 40.3 (32.3-48.3) 0.06 (0.04-0.08) 50-54 30.1 (23.0-37.2) 0.04 (0.03-0.05) 55-59 28.0 (22.3-33.7) 0.04 (0.03-0.05) 60-64 24.8 (19.0-30.6) 0.03 (0.02-0.04) 65-69 27.7 (21.3-34.1) 0.03 (0.02-0.05) 70-74 16.8 (11.0-22.6) 0.02 (0.01-0.02) 75-79 20.7 (12.7-28.7) 0.02 (0.01-0.03) (a) CI, confidence interval. Both for orthodox reformed persons less than 50 years and for those at least 50 years of age, the proportion with no protection was higher than for persons in the nationwide sample (Table 4). Table 4. Diphtheria immunity in a nationwide sample and in orthodox reformed persons in municipalities with low vaccine coverage, the Netherlands.
Sample(a) <0.01 0.01-0.1
(yrs) No. IU/ml (95% CI(b)) IU/ml
NW
0-49 5,064 5.3 (4.4-6.2) 27.3
50-79 2,651 29.2 (26.4-31.9) 37.4
ORLVC
0-49 170 60.8 (40.2-81.4) 7.4
50-79 63 59.3 (30.1-88.6) 34.6
[is greater than
Sample(a) or equal to]
(yrs) (95% CI) IU/ml (95% CI)
NW
0-49 (25.3-29.4) 67.4 (65.2-69.5)
50-79 (35.3-39.5) 33.4 (31.3-35.6)
ORLVC
0-49 (2.3-12.6) 31.8 (13.8-49.7)
50-79 (9.5-59.6) 6.1 (0.0-18.2)
Geometric
Sample(a) mean
(yrs) titer (95% CI)
NW
0-49 0.17 (0.16-0.19)
50-79 0.04 (0.04-0.05)
ORLVC
0-49 0.02 (0.01-0.05)
50-79 0.01 (0.005-0.025)
(a) NW, nationwide; ORLVC, Orthodox reformed from low vaccine coverage sample. (b) CI, confidence interval. Men and women ages 20 to 49 years without a military service history had similar proportions of full, basic, and no protection, while the proportion with full protection was higher for men with a military service history (Table 5). Table 5. Diphtheria immunity in a nationwide sample among persons 20 to 49 years of age, according to sex and military service, the Netherlands
<0.01 0.01-0.1
Sample(a) No. IU/ml (95% CI(b)) IU/ml
M, SH 425 2.9 (1.2-4.6) 14.9
M, NSH 710 7.8 (5.2-10.3) 33.1
W, NSH 1,456 9.1 (7.0-11.2) 32.5
[is greater than
or equal to]
Sample(a) (95% CI) IU/ml (95% CI)
M, SH (11.1-18.7) 82.2 (78.0-86.5)
M, NSH (28.0-38.1) 59.2 (54.0-64.4)
W, NSH (29.0-36.0) 58.4 (54.5-62.3)
Geometric
mean
Sample(a) titer (95% CI)
M, SH 0.30 (0.25-0.36)
M, NSH 0.12 (0.10-0.14)
W, NSH 0.12 (0.10-0.13)
(a) M, men; W, women; SH, service history; NSH NSH nutritional secondary hyperparathyroidism. , no service history. (b) CI, confidence interval. Persistence of Diphtheria Antitoxin Levels The geometric mean titer decreased with age (or time since last vaccination) for persons who had received their sixth and last vaccination at 8 to 9 years of age (n = 961) from 0.30 IU/ml for 10 to 14 years to 0.09 IU/ml for 30 to 34 years (Table 6, Figure 2). According to linear regression analysis, the decrease corresponds to a decrease of -1.27 [sup.2]log IU/ml with each [sup.2]log increase in years. The percentage with full protection decreased from 82.5% to 41.7%, and the percentage with no protection increased from 0% to 4.3% for persons 10 to 14 years of age and 30 to 34 years of age, respectively (Table 6). [Figure 2 ILLUSTRATION OMITTED] Table 6. Diphtheria immunity for persons in a nationwide sample who were completely vaccinated in the national immunization program and received the sixth diphtheria vaccination at 8 or 9 years of age, the Netherlands
Sample(a) <0.01 0.01-0.1
(yrs) No. IU/ml (95% CI(b)) IU/ml
NRE
10-14 392 0.0 -- 17.5
15-19 282 0.4 (0.0-1.3) 30.1
20-24 155 1.2 (0.0-3.0) 29.4
25-29 80 1.6 (0.0-3.7) 28.3
30-34 52 4.3 (0.0-9.2) 54.0
RE
20-34 37 0.0 -- 19.0
[is greater than
or equal to]
Sample(a) (95% CI) IU/ml (95% CI)
(yrs)
NRE
10-14 (12.8-22.1) 82.5 (77.9-87.1)
15-19 (23.7-36.5) 69.4 (63.2-75.7)
20-24 (20.7-38.2) 69.4 (60.7-78.1)
25-29 (17.2-39.4) 70.2 (58.7-81.6)
30-34 (39.3-68.8) 41.7 (27.3-56.1)
RE
20-34 (3.2-34.9) 81.0 (65.1-96.8)
Geometric
Sample(a) mean titer
(yrs) (IU/ml) (95% CI)
NRE
10-14 0.30 (0.26-0.34)
15-19 0.17 (0.14-0.21)
20-24 0.16 (0.12-0.19)
25-29 0.14 (0.11-0.18)
30-34 0.09 (0.07-0.13)
RE
20-34 0.29 (0.18-0.46)
(a) NRE (Non-Recurring Engineering) Refers to the cost of creating a new product, which is paid up front. Contrast with "production cost," which is ongoing and based on the quantity of material produced. , no evidence of revaccination; RE, evidence of revaccination. (b) CI, confidence interval. The geometric mean titer for persons 20 to 34 years of age with documented revaccination (n = 37) was 0.29 IU/ml. Percentages of full (81.0%), basic (19.0%), and no protection (0.0%) were similar to recently vaccinated 10- to 14-year-olds, without further documented or reported revaccination (Table 6). Conclusions Our population-based study showed that 58% of the Dutch population had full, 30% basic, and 12% no protection against diphtheria. These estimates and the geometric mean titer (0.12 IU/ ml) are in between findings for other European countries (4,11-20). The Dutch immunization program appeared to induce long-term protection. However, approximately one third of adults age 50 to 79 years, who were born before the introduction of the immunization program, and approximately two-thirds of orthodox reformed persons had no protective diphtheria antibodies. The toxin inhibition test used to measure diphtheria antitoxin concentrations shows good correlation with the in vitro in vitro /in vi·tro/ (in ve´tro) [L.] within a glass; observable in a test tube; in an artificial environment. in vi·tro adj. In an artificial environment outside a living organism. neutralization test neutralization test n. See protection test. in Vero cells Vero cells are lineages of cells used in cell cultures.[1] The Vero lineage was isolated from kidney epithelial cells extracted from African green monkey (Cercopithecus aethiops). , but is faster, simpler, and combines the measurement of diphtheria and tetanus antitoxin tetanus antitoxin n. The antitoxin specific for the neurotoxin produced by Clostridium tetani. antibodies (8,9). Although the participation rates in the nationwide sample and low vaccine coverage sample were 55% and 52.5%, respectively, our population-based estimates of diphtheria immunity were considered representative, because they do not seem to be affected by nonparticipation. Our participants included a large percentage of persons with diphtheria protection who were born after the vaccination was introduced in 1952 and after the virtual disappearance of diphtheria in 1960. High levels of immunity in this group reflect the success of the national vaccination program. For persons born before the introduction of vaccination, diphtheria immunity is largely derived from natural infection. However, immunity levels in persons older than 49 years in the general population are higher than those of orthodox reformed persons, suggesting that immunity was partly induced by vaccinations (e.g., for military service, travel). The sharp increase in the percentage of persons older than 44 years with no protective diphtheria antitoxin levels is consistent with findings of other studies (4,11,12,14-19). The increase supports the phenomenon of waning immunity after natural infection without boosting. In our study, higher immunity levels among men are associated with military service, as previously reported (15,19). However, some researchers have found similar immunity levels for men and women, while others have reported lower immunity for men (11,16,21). Furthermore, lower immunity for women that could not be ascribed to vaccinations during military service has also been reported (4,20). Women might maintain immunity after vaccination for a shorter time than men (14). The slightly lower geometric mean titers for girls age 5 to 19 years in our study are consistent with the latter possibility. As more than 60% of orthodox reformed persons have no protection against diphtheria, introduction of diphtheria into this group may constitute a danger of spreading the bacterium. Since the Netherlands does not have a mandatory vaccination policy Vaccination policy refers to the policy a government practices in relation to vaccination. Vaccinations are voluntary in some countries and mandatory in some countries. Some governments pay all or part of the costs of vaccinations for vaccines in a national vaccination schedule. , protection of persons who refuse vaccination is problematic. For poliomyelitis the solution seems to be eradication eradication extermination of an infectious agent so that no further cases of the related disease can occur. virtual eradication of the causative caus·a·tive adj. 1. Functioning as an agent or cause. 2. Expressing causation. Used of a verb or verbal affix. caus agent (5). For diphtheria such a goal has not yet been formulated by WHO. However, even though systematic assessment has not been performed, no signs of persistent circulation of C. diphtheriae Noun 1. C. diphtheriae - a species of bacterium that causes diphtheria Corynebacterium diphtheriae, Klebs-Loeffler bacillus corynebacterium - any species of the genus Corynebacterium exist in the Netherlands. When our data are interpreted longitudinally, the log linear decrease in diphtheria antibody level with age for completely vaccinated persons corresponds with a continuous decline in vaccine-induced antibodies (13,22). However, relatively few 30- to 34-year-old persons (4.3%) who received their last vaccination approximately 25 years ago had a diphtheria antitoxin level of less than 0.01 IU/ml. This compares favorably fa·vor·a·ble adj. 1. Advantageous; helpful: favorable winds. 2. Encouraging; propitious: a favorable diagnosis. 3. with observations in other countries (13,21-23). Our immunization program, in which children are vaccinated at 3, 4, 5, and 11 months with 15 Lf diphtheria toxoid toxoid, protein toxin treated by heat or chemicals so that its poisonous property is destroyed but its capacity to stimulate the formation of toxin antibodies, or antitoxins, remains. and at the ages of 4 and 9 years with 2.5 Lf, appears to induce long-term protection against diphtheria. In the Netherlands, booster Booster - A data-parallel language. "The Booster Language", E. Paalvast, TR PL 89-ITI-B-18, Inst voor Toegepaste Informatica TNO, Delft, 1989. vaccinations are only advised for persons at increased risk for exposure (e.g., travelers to endemic-disease countries and those who work with injection drug users and alcoholic patients). The need for routine boosters to guarantee population protection depends mainly on the proportion of vaccinated persons necessary to confer diphtheria herd immunity. This proportion is estimated at 70% to 80%, but no antitoxin level has been precisely defined for complete protection (10,13,24-26). The Dutch immunity level exceeds this threshold (a minimum level of 0.01 IU/ml [88%]), but is below a minimum level of 0.1 IU/ml (58%). The absence of cases in the Netherlands associated with the diphtheria epidemic in Eastern Europe suggests that herd immunity is sufficient. This herd immunity might result from sufficient protective levels of antitoxin or immunologic immunologic, immunological emanating from or pertaining to immunology. immunologic competence see immunocompetence. immunologic domains memory. Our results, like those of others, indicate good immunologic memory after revaccination for persons who had been previously vaccinated (17, 27). However, the memory response of adults after initial vaccination is unknown. Furthermore, unknown protective mechanisms might be involved. Only sporadic cases and no outbreaks have occurred in other European countries where gaps have been found in the diphtheria antitoxin levels of adults. The only recent epidemic in western Europe Western Europe The countries of western Europe, especially those that are allied with the United States and Canada in the North Atlantic Treaty Organization (established 1949 and usually known as NATO). , which occurred before the epidemic in eastern Europe, was among alcoholics (23). Perhaps unfavorable social conditions, like those that appear to have contributed to the epidemics in eastern Europe, play a role in the spread of diphtheria. In conclusion, a substantial percentage of adults born before the introduction of the immunization program has low diphtheria antitoxin levels. Although herd immunity seems sufficient, long-term population protection cannot be assured. Possibly vaccination might fill the gaps of diphtheria antitoxin antibodies. Diphtheria vaccination could be efficiently combined with other vaccines (e.g., tetanus, influenza influenza or flu, acute, highly contagious disease caused by a virus; formerly known as the grippe. There are three types of the virus, designated A, B, and C, but only types A and B cause more serious contagious infections. ) as part of an adult immunization adult immunization The administration of vaccines to prevent clinical infection in adulthood; 'The contrast between the impact of vaccine- preventable diseases of adults compared with those of children is striking. Each yr, < 500 persons in the U.S. program. Acknowledgments We thank the Public Health Services health services Managed care The benefits covered under a health contract , the Pienter Project Team, and C.J.P. van Limpt and H.A.T. Kuijken for their useful contributions. We also thank J. Huisman, H.C. Rumke, J.F.P. Schellekens, and J.K. van Wijngaarden for their valuable comments on our manuscript. References (1.) Hardy IRB IRB See: Industrial Revenue Bond , Dittmann S, Sutter RW. Current situation and control strategies for resurgence of diphtheria in newly independent states New·ly Independent States Abbr. NIS The countries that until 1991 were constituent republics of the USSR, including Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Tajikistan, Turkmenistan, Ukraine, and Uzbekistan. of the former Soviet Union. Lancet lancet /lan·cet/ (lan´set) a small, pointed, two-edged surgical knife. lan·cet n. 1996;347:1739-44. (2.) World Health Organization. The expanded programme on immunisation in the European Region of WHO. Diphtheria. Plan of action for the prevention and control of diphtheria in the European Region (1994-1995). Copenhagen, 1994. ICP/EP1038 (A). (3.) Prospero E, Raffo M, Bagnoli M, Appignanesi R, D'Errico M. Diphtheria: epidemiological update and review of prevention and control strategies. Eur J Epidemiol 1997;13:527-34. (4.) Maple PA, Efstratiou A, George RC, Andrews NJ, Sesardic D. Diphtheria immunity in UK blood donors. Lancet 1995;345:963-5. (5.) Oostvogel PM, van Wijngaarden JK, van der Avoort HGAM, Mulders MN, Conyn-van Spaendonck MAE (1) (Metropolitan Area Exchange) Originally known as Metropolitan Area Ethernets, MAEs are junction points on the Internet where data is exchanged between carriers. See IXP and NAP. , Rumke HC, et al. Poliomyelitis outbreak in an unvaccinated community in the Netherlands, 1992-93. Lancet 1994;344:665-70. (6.) de Melker HE, Conyn-van Spaendonck MAE. Immunosurveillance and the evaluation of national immunisation programmes: a population-based approach. Epidemiol Infect infect /in·fect/ (in-fekt´) 1. to invade and produce infection in. 2. to transmit a pathogen or disease to. in·fect v. 1. 1998;21:637-43. (7.) Cochran WG. Sampling techniques. 3rd ed. New York New York, state, United States New York, Middle Atlantic state of the United States. It is bordered by Vermont, Massachusetts, Connecticut, and the Atlantic Ocean (E), New Jersey and Pennsylvania (S), Lakes Erie and Ontario and the Canadian province of : John Wiley John Wiley may refer to:
(8.) Hendriksen CFM (Cubic Feet per Minute) The measurement of air flow. Cooling fans are rated in CFM. , van de Gun JW, Kreefcenberg JG. Combined estimation of tetanus and diphtheria antitoxin in human sera by the in vitro Toxin Binding Inhibition (ToBI) test. Journal of Biological Standardization standardization In industry, the development and application of standards that make it possible to manufacture a large volume of interchangeable parts. Standardization may focus on engineering standards, such as properties of materials, fits and tolerances, and drafting 1989;17:191-200. (9.) Knipping CT, Berbers GAM. Vergelijkingvan de Toxine Bindings Inhibitie test (ToBI) met de Dubbel Antigeen ELISA (DAE See digital audio extraction. ) voor het bepalen van antistoftiters gericht tegen difterie toxine in humaan serum. RIVM RIVM Rijksinstituut voor Volksgezondheid en Milieu report no. 126000001,1998, Bilthoven, the Netherlands. (10.) Galazka AM. The immunological immunologic, immunological emanating from or pertaining to immunology. immunologic competence see immunocompetence. immunologic domains basis for immunisation. Diphtheria. Geneva Geneva, canton and city, Switzerland Geneva (jənē`və), Fr. Genève, canton (1990 pop. 373,019), 109 sq mi (282 sq km), SW Switzerland, surrounding the southwest tip of the Lake of Geneva. : World Health Organization. Geneva; 1993. WHO/EPI/GEN/93.12. (11.) Stark K, Barg J, Molz B, Vormwald A, Bienzle U. Immunity against diphtheria in blood donors in East Berlin and West Berlin. Lancet 1997;350:932. (12.) Mathei C, van Damme P, Bruynseels P, Geossens H, Vranckx R, Metheus A. Diphtheria immunity in Flanders. Eur J Clin Microbiol Infect Dis 1997;16:631-6. (13.) Simonsen O, Kjeldsen K, Bentzon MW, Heron I. Susceptibility susceptibility the state of being susceptible. Refers usually to infectious disease but may be to physical factors such as wetting or to psychological factors such as harassment. to diphtheria in populations vaccinated before and offer elimination of indigenous diphtheria in Denmark. A comparative study of antitoxic an·ti·tox·ic adj. 1. Neutralizing the action of a toxin or poison. 2. Of, relating to, or containing an antitoxin. antitoxic, adj having the capacity to render bacterial toxins inert. immunity. Acta Pathol Microbiol Immunol Scand Sect C 1987;95:225-31. (14.) Kjeldsen K, Simonsen O, Heron I. Immunity against diphtheria and tetanus in the age group 30-70 years. Scand J Infect Dis 1988;20;177-85. (15.) Jenum PA, Skogen V, Danilova E, Eskild A, Sjursen H. Immunity to diphtheria in northern Norway and northwestern Russia. Eur J Clin Microbiol Infect Dis 1995;14:794-8. (16.) Klouche M, Luhmann D, Kirchner H. Low prevalence of diphtheria antitoxin in children and adults in northern Germany Northern Germany is the geographic area in the north of Germany. The native German concept of northern Germany is called Norddeutschland. Northern German States Norddeutschland is the geographic area of five German states:
(17.) World Health Organization. Expanded programme on immunization. Immunization of adults against diphtheria. Wkly Epidemiol Rec 1995;70:56-9. (18.) World Health Organization. Expanded programme on immunization. Diphtheria immunity in the adult French population. Wkly Epidemiol Rec 1995;70:252-5. (19.) Gasparini R, Pozzi T, Fragapane E, Severini R, Cellesi C, Fabrizi P, et al. Immunity to diphtheria in Siena. Epidemiol Infect 1997;119:203-8. (20.) Miller E, Rush M, Morgan-Capner P, Hutchinson D, Hindle L. Immunity to diphtheria in adults in England. BMJ BMJ n abbr (= British Medical Journal) → vom BMA herausgegebene Zeitschrift 1994;308:598. (21.) Cellesi C, Michelangeli C, Rossolini GM, Giovannoni F, Rossolini A. Immunity to diphtheria, six to 15 years after a basic three-dose immunization schedule. Journal of Biological Standardization 1989;17:29-34. (22.) Kjeldsen K, Simonsen O, Heron I. Immunity against diphtheria 25-30 years after primary vaccination in childhood. Lancet 1985; 1:900-2. (23.) Bottiger M, Pettersson G. Vaccine immunity to diphtheria: a 20-year follow-up study. Scand J Infect Dis 1992;24:753-8. (24.) Anderson RM, May RM. Infectious diseases infectious diseases: see communicable diseases. of humans: dynamics and control. 2nd ed. New York: Oxford University Press; 1991. (25.) Ipsen J. Circulating cir·cu·late v. cir·cu·lat·ed, cir·cu·lat·ing, cir·cu·lates v.intr. 1. To move in or flow through a circle or circuit: blood circulating through the body. 2. antitoxin at the onset of diphtheria in 425 patients. J Immunol 1946;54:325-47. (26.) Schneerson R, Robbins JB, Taranger J, Lagergard T, Trollfors B. A toxoid vaccine for pertussis as well as diphtheria? Lessons to be relearned. Lancet 1996;348:1289-92. (27.) Simonsen O, Kjeldsen K, Vendborg HA, Heron I. Revaccination of adults against diphtheria I: response and reactions to different doses of diphtheria toxoid in 30-70-year-old persons with low serum antitoxin levels. Acta Pathol Microbiol Immunol Scand Sect C 1986;94:213-8. H.E. de Melker is an epidemiologist in the Department of Infectious Diseases Epidemiology, National Institute of Public Health and the Environment, the Netherlands. Her work involves epidemiologic research directed to vaccine-preventable diseases and evaluation of the national vaccination program. Address for correspondence: H.E. de Melker, National Institute of Public Health and the Environment, Department of Infectious Diseases Epidemiology, P.O. Box 1, 3720 BA Bilthoven, The Netherlands; fax: 31-30-274-4409; e-mail: H.de.Melker@rivm.nl. |
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