Download Implications of the Diphtheria Epidemic in the Former Soviet Union

S244
Implications of the Diphtheria Epidemic in the Former Soviet Union
for Immunization Programs
Artur Galazkaa
National Institute of Hygiene, Warsaw, Poland
The massive diphtheria epidemic in the former Soviet Union provides important lessons
for all diphtheria immunization programs: It is important to achieve a high level of childhood
immunization, maintain immunity against diphtheria in older age groups, and use anti-epidemic measures, including immunization, to control epidemics in the early phase. The immunization coverage among children should be at least 90%. Further studies are needed to
elaborate the most effective strategy to maintain immunity against diphtheria in adults (periodic booster doses, immunization of selected age groups in health care settings, use of Td
[tetanus-diphtheria toxoids with reduced diphtheria toxoid content] vaccine instead of monovalent tetanus toxoid whenever tetanus toxoid is indicated [e.g., in treatment of wounds or
in school-based immunization programs]). Efforts should be undertaken to monitor diphtheria
immunity in different groups by conducting age-specific serologic studies.
The epidemic of diphtheria in the Newly Independent States
(NIS) of the former Soviet Union is the largest outbreak in the
developed world in recent years and was considered by the
World Health Organization (WHO) as an international public
health emergency [1–4]. Since the epidemic began, 1150,000
cases and 4500 deaths, representing 190% of all diphtheria cases
reported worldwide during 1990–1995, have been reported to
the WHO Regional Office for Europe [5].
The NIS epidemic provides three important lessons for diphtheria immunization programs. These lessons are related to
childhood immunization, the need for maintaining immunity
in older age groups, and the use of immunization in controlling
epidemics. These three issues are discussed herein.
The Importance of Childhood Immunization
Analysis of the NIS diphtheria epidemic suggests that the
potential for severe outbreaks of diphtheria is enhanced when
a large proportion of susceptible adults and unimmunized children coexist in the same community. In the mid-1970s, the
incidence of diphtheria among children in Russia was very
low, with the lowest number of cases (52–57) registered in
1975–1976. Then, in the mid-1980s, the incidence began to increase, especially in preschool-aged children. The changes were
clearly seen in Moscow, where the epidemic started (figure 1).
During the 1980s, changes in the immunization schedule in
the former Soviet Union encouraged less intensive immunization of children [3]. By 1992, the epidemic was characterized
a
Deceased.
Reprints or correspondence: Dr. Sieghart Dittmann, International Immunization Consulting, Hatzenporter Weg 19, 12681 Berlin, Germany
([email protected]).
The Journal of Infectious Diseases 2000; 181(Suppl 1):S244–8
q 2000 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2000/18102S-0040$02.00
by an increased incidence in all age groups, with the peak incidence in 5- to 10-year-old children and 30- to 50-year-old
adults [2, 4]. This paralleled a country-wide drop in infant immunization coverage: During the late 1980s and the early 1990s,
the reported coverage with a primary series of diphtheria toxoid–containing vaccine among 1-year-old children and with
booster doses varied between 60% and 80% (table 1). However,
in many urban areas, including Moscow and St. Petersburg,
the diphtheria immunization coverage rates in infants were very
low (range, 18%–59%) [7–10]. The drop in coverage was due
to decreased public support for the childhood vaccination program, a vocal anti-immunization movement, and insufficiently
motivated and improperly trained health care workers, especially at the primary health care level. An excessive list of contraindications named 150 specific diagnoses that precluded
the administration of the diphtheria-tetanus toxoids–pertussis
(DTP) vaccine [11], and a long list of permanent and temporary
contraindications to immunization was used by specialists who
are consultants for vaccination and who delayed immunization
of children for long periods [6].
The general public lost confidence in immunization due to
opinions of health care workers and to increasing and aggressive antivaccination propaganda in the mass media. In addition,
large cohorts of children (up to 50%) were immunized with Td
vaccine (tetanus-diphtheria toxoids vaccine with a reduced
content of diphtheria compared with that in DTP) instead
of DTP vaccine, due to unjustified overestimation of vaccine
complications.
The diphtheria epidemic than began in Ukraine in 1992 has
also been attributed to a significant decrease in immunization
coverage in children [12]. The experiences of two of Russia’s
neighbors, Poland and Finland, provide another example of
the importance of high immunization coverage among children.
In these two countries, very high levels (195%) of childhood
immunization against diphtheria have been maintained for a
JID 2000;181 (Suppl 1)
Immunization against Diphtheria
Figure 1.
Incidence of diphtheria per 100,000 population, by
age—Moscow, 1980, 1985, and 1990. Data from the Ministry of Health.
long period. In Poland, despite a high influx of visitors from
infected areas (Belarus, Ukraine, and Russia) and visits of Polish citizens to epidemic areas in the NIS, only 25 cases of
diphtheria, mostly in young adults, with no secondary transmission were reported from 1992 to 1996 [13, 14]. In Finland,
there was no secondary transmission of infection despite documented reports of disease importations [15].
Need for Maintenance of Immunity against Diphtheria
among Older Age Groups
The gap in diphtheria immunization of adults is well documented in industrialized countries (table 2) [22–26], and it is
important to close this gap with well-spaced booster doses of
diphtheria toxoid. However, the routine use of such booster
doses remains a controversial issue. Many countries recommend life-long immunization of adults with booster doses of
diphtheria toxoid–containing vaccine at intervals of 10–20
years. A routine booster dose of Td vaccine is recommended
every 10 years in many countries, including Australia [27],
Canada [28], Germany [29], Italy [29], Austria [30], and the
United States [31]. Td vaccine is recommended in adults in NIS
countries and in Bulgaria (at 25 and 35 years of age) [32].
Several European countries have added extra doses of diph-
S245
theria toxoid–containing vaccines in their school-based immunization programs and for travelers [29]. A study in Denmark suggested that long-term protection may be assured by
a booster dose of Td vaccine administered 20 years after primary immunization [33]. In 1989–1990, on the basis of serosurveys indicating low antibody levels in persons 140 years of
age [29], Finland initiated a mass vaccination campaign targeted at adults.
The strategy of spaced boosters has not been effectively implemented in any country. Routine decennial booster doses of
Td vaccine for adults are difficult to monitor, and usually this
strategy is only marginally effective. An alternative approach
could be an immunization strategy that would be age-specific
for ages at which people often contact health care providers
(e.g., at 20 and 50 years of age). The choice of strategy depends
on multiple local conditions and can be done only at the country level. In countries where the risk of diphtheria is considered
high, periodic booster doses for adults will be indicated to prevent the resurgence of diphtheria in adults as immunity wanes.
In other countries, adult diphtheria booster strategies need to
be considered in the light of the perceived risk of diphtheria,
the opportunities that exist for provision of booster vaccinations, and the sensitivity of surveillance so that rapid responses
can be implemented should diphtheria be introduced.
In the United States, there was a debate on the appropriate
frequency of tetanus immunization in adults [34–37]. It was
argued that the current recommendation to give Td vaccine
every 10 years throughout adulthood has failed and may not
be cost effective [34, 35]. It was proposed to forsake decennial
boosters in favor of a policy of including a single booster at
age 65 along with other recommended health procedures reserved for that age group [34]. However, the analysis was limited
to tetanus and did not include diphtheria toxoid policy. There
are essential differences between these two models: Tetanus has
now become a geriatric disease, while, as we learned from the
diphtheria epidemic in the NIS, 30- to 50-year-old persons are
at high risk for diphtheria. In 1993, the Advisory Committee
on Immunization Practices (ACIP) reviewed the current status
of tetanus and diphtheria in the United States and evaluated
four options for vaccine use: (1) a single adult booster vaccine
at age 65 years; (2) two adult booster vaccine doses, given at
15 and 55 years of age; (3) adult booster vaccine doses given
every 20 years; and (4) no change from the current recommenTable 1. Percentage of diphtheria vaccination coverage in various
age groups, Russian Federation. 1989–1994.
% coverage
Age, years
1989
1990
1991
1992
1993
1994
1
3
10
14
16
82.7
77.2
86.0
84.8
—
68.5
77.3
87.5
68.6
—
69.1
74.6
88.1
81.7
83.4
72.6
81.3
88.3
86.0
80.1
79.2
83.0
92.4
—
86.5
88.1
97.5
98.9
92.4
97.1
NOTE.
According to Narkevich and Tymchakovskaya [6].
S246
Galazka
Table 2.
Percentage of persons immune to diphtheria, by age, in various European countries, 1989–1997.
a
Age, years
Belgium
!10
10–19
20–29
30–39
40–49
50–59
60–64
>65
Population
studied
95.0
90.4
67.3
42.1
44.5
68.6
Reference
a
b
c
JID 2000;181 (Suppl 1)
57.4
General surgery,
trauma, and
emergency ward
patients
Mathei et al.,
1997 [16]
a
Denmark
b
a
a
Germany
Italy
Lithuania
90
100
90
95
87
65
50
100
92.5
85.0
46.2
57.5
66.7
61.5
98
98
46
46
46
Military recruits
Healthy blood
donors and
surgical patients
Healthy persons
Aggerbeck et al.,
1995 [17]
Klouche et al.,
1995 [18]
Wirz et al.,
1995 [19]
72.2
a
Sweden
c
United Kingdom
Military personnel
83
83
47
47
53
53
53
Medical staff
74
74
68
68
68
57
57
Diagnostic samples, residuals
Rix et al.,
1994 [20]
Bjorkholm et al.,
1989 [21]
Miller et al.,
1994 [22]
% of persons with titers 10.01 IU/mL as determined by tissue culture neutralization test.
% of persons with titers 10.01 IU/mL as determined by ELISA.
% of persons with titers 10.1 IU/mL as determined by ELISA.
dations with decennial booster doses. The ACIP endorsed option 4 [37].
One strategy can be helpful in maintaining immunity against
diphtheria in adults: Td vaccine can be used instead of monovalent tetanus toxoid whenever tetanus toxoid is indicated (e.g.,
in treating wounds or in school-based programs for administering booster doses of tetanus toxoid) [32, 38], and it can be
used in high-risk groups likely to be exposed to diphtheria
infection and identified by age, geographic distribution, or profession (e.g., health care, military, or school personnel and students, alcohol and drug abusers, and persons traveling to areas
where diphtheria is endemic or epidemic).
On the basis of available data, at least 70% of adults who
receive a booster dose of diphtheria toxoid (Td vaccine) respond
with a protective level of diphtheria antibodies [39]. Similar
results were obtained in studies done in adults in Odessa,
Russia, and Kiev, Ukraine, with Td vaccine containing 2–5 limit
of flocculation units of diphtheria toxoid [5].
The Use of Immunization to Control the Epidemic
The NIS epidemic was unexpected for local health authorities, who denied the existence of the epidemic during the first
years, 1990–1992. The delay in undertaking rapid and adequate
anti-epidemic measures during the early stages of the epidemic,
when it was “localized,” was one of the factors influencing the
extent and duration of the epidemic. The epidemic could have
been stopped more easily and more quickly if control measures
had been implemented earlier. The epidemic was declared such
in 1993, when the number of cases exceeded 15,000 and the
infection had spread over vast areas [6].
The importance of rapid anti-epidemic actions was shown in
the epidemic of diphtheria among adults in Hubei Province,
China [40]. A rapid immunization campaign with one dose of
diphtheria toxoid was conducted during 2 months and covered
75% of persons 17 years of age (102,376/136,530 total popu-
lation). After a vaccination campaign, diphtheria transmission
declined rapidly.
During the last 4 years, intensified efforts were undertaken
in the Russian Federation and other NIS to control the diphtheria epidemic. Countries adopted a strategy for one dose of
vaccine to be administered in the shortest possible period of
time to all children, adolescents, and adults, regardless of individual immunization histories. As a modification to this strategy, specific age cohorts with low levels of immunity (e.g., 30to 50-year-old adults) received a full 3-dose primary series of
Td vaccine. The list of medical contraindications to vaccination
was reexamined and shortened, immunization schedules were
revised, and the mass media were more widely used for spreading information about the epidemic and about the need for
vaccination. Most NIS countries have made strenuous efforts
to improve early diagnosis and treatment of cases. By the end
of 1995 in the Russian Federation, 70%–80% of adults (>18
years of age) had had at least one dose of vaccine, compared
with an estimated 20% coverage in 1990. The reported nationwide coverage with a primary series of diphtheria toxoid among
12- to 23-month-old children was 92.7% in 1995 [1]. The total
number of vaccinated persons increased from 11.7 million in
1992 to 20.2 million (including 13.6 million adults) in 1993 and
to 37.7 million (29.6 million adults) in 1994 [6].
Lessons Learned from the Diphtheria Epidemic
The return of epidemic diphtheria throughout the NIS after
130 years of successful control and the spread of infection to
many European countries and Mongolia provides important
lessons for diphtheria immunization programs:
• The achievement of high immunization coverage (190% of
the population) with a primary series of three doses of DTP
vaccine is of utmost importance. A primary course should
start soon after birth, preferably at 2 months of age, and
respect the minimal interval of 4 weeks between doses. The
JID 2000;181 (Suppl 1)
•
•
•
•
•
Immunization against Diphtheria
primary course should be completed before 6 months of
age. For the primary immunization, only a full-strength
pediatric-type of diphtheria vaccine (administered as DTP)
should be used.
The use of a fourth dose of DTP vaccine in preschool-age
children is recommended in countries that have achieved
high coverage with the primary series. The age for a fourth
dose should be selected after a careful analysis of the age
distribution of cases of diphtheria, pertussis, and tetanus
in a given area. Usually, it is given between 12 and 36
months of age. The immunization coverage with this dose
should also exceed 90%. The need for an additional booster
(fifth) dose of DTP vaccine should be assessed by individual
national programs.
Immunization of school-aged children is recommended.
For children immunized in infancy with DTP or DT (diphtheria-tetanus toxoids) vaccines, a booster dose is recommended when they enter and, preferably, when they leave
school. In children !7 years of age, DT vaccine should be
used, and in older children, Td vaccine is indicated.
Countries that have successfully controlled diphtheria
through infant and childhood immunization programs
should maintain immunity against diphtheria in adults by
the use of Td vaccine (or d vaccine, an adult-type monovalent diphtheria toxoid for persons with a high immunity
against tetanus). The choice of strategies depends on local
conditions; Td vaccine can be given as periodic booster
doses every 10–20 years, or the selected strategy can be
age-specific for ages at which people are in contact with
health care providers. Periodic booster doses are indicated
in countries where the risk of introducing diphtheria is
considered high. The maintenance of immunity against
diphtheria in adults can be facilitated by using Td vaccine
instead of monovalent tetanus toxoid vaccine when tetanus
toxoid is indicated in the treatment of wounds and by wider
use of Td vaccine in high-risk groups (e.g., military and
health care personnel, kindergarten and school teachers,
students, and drug and alcohol abusers).
In the face of the diphtheria epidemic, anti-epidemic measures should be undertaken rapidly and without delay,
when transmission of Corynebacterium diphtheriae organisms is limited to specific organizational groups. The strategy that proved effective in the NIS epidemic was mass
immunization of the entire population with at least one
dose of diphtheria toxoid–containing vaccine, regardless of
the previous immunization history, and two additional
doses for specific age groups with low-level immunity (e.g.,
30- to 50-year-old adults).
Special efforts should be undertaken to monitor diphtheria
immunity in different groups by conducting age-specific
serologic studies. In countries where diphtheria is successfully controlled and where there are no diphtheria cases,
results of serologic testing are important for assessing the
S247
risk of diphtheria. In countries where diphtheria cases are
still being reported, changes in age distribution of cases
and trends in diphtheria incidence are useful factors for
assessing the risk. In NIS countries, serologic testing was
being excessively relied upon as a means of routine monitoring in each oblast (region). Given the cost and the staff
time required, serologic testing should be reserved as a tool
for specially designed and carefully executed studies aimed
at identifying gaps in immunity in certain age groups.
References
1. WHO Expanded Programme on Immunization. Update: Diphtheria epidemic in the Newly Independent States of the former USSR, January
1995–March 1996. Wkly Epidemiol Rec 1996; 71:245–50.
2. Hardy I, Dittmann S, Sutter R. Current situation and control strategies for
resurgence of diphtheria in Newly Independent States of the former Soviet
Union. Lancet 1996; 347:1739–44.
3. Vitek CR, Wharton M. Diphtheria in the former Soviet Union: reemergence
of a pandemic disease. Emerg Infect Dis 1998; 4:539–50.
4. Galazka AM, Robertson SE, Oblapenko GP. Resurgence of diphtheria. Eur
J Epidemiol 1995; 11:95–105.
5. Dittmann S. Epidemic diphtheria in the Newly Independent States of the
former USSR—situation and lessons learned. Biologicals 1997; 25:179–86.
6. Narkevich MI, Tymchakovskaya IM. Specific features of diphtheria in Russia in the presence of mass immunization of children [in Russian]. Zh
Mikrobiol Epidemiol Immunol 1996; 2:25–9.
7. Lytkina IN, Leshkevitsch R. Mass immunization against diphtheria in Moscow and its prophylaxis [in Russian]. In: Proceedings of the meeting on
the Diphtheria Epidemic in Europe (St. Petersburg, 5–7 July 1993). Lyon:
Fondation Marcel Mérieux and Copenhagen: World Health Organization,
1993:64–8.
8. Monisov AA, Waganov NN. Diphtheria in Russia [in Russian]. In: Proceedings of the meeting on the Diphtheria Epidemic in Europe (St. Petersburg, 5–7 July 1993). Lyon: Fondation Marcel Mérieux and Copenhagen: World Health Organization, 1993:21–9.
9. Okuneva MA, Voronov IM. Experience in mass immunization in St. Petersburg [in Russian]. In: Proceedings of the meeting on the Diphtheria
Epidemic in Europe (St. Petersburg, 5–7 July 1993). Lyon: Fondation
Marcel Mérieux and Copenhagen: World Health Organization, 1993:61–3.
10. WHO Expanded Programme on Immunization: impact of immunization
programme, USSR. Wkly Epidemiol Rec 1986; 61:221–2.
11. Sadovnikova WN, Zhilina HJ. Mass immunization [in Russian]. In: Proceedings on the meeting of the Diphtheria Epidemic in Europe (St. Petersburg, 5–7 July 1993). Lyon: Fondation Marcel Mérieux and Copenhagen: World Health Organization, 1993:58–60.
12. WHO Expanded Programme on Immunization. Diphtheria epidemic.
Ukraine. Wkly Epidemiol Rec 1994; 69:253–8.
13. Galazka A, Tomaszunas J, Blaszczyk J. Why do adults contract diphtheria?
EuroSurveillance 1997; 2:60–3.
14. WHO Expanded Programme on Immunization. Recrudescence of diphtheria. Poland. Wkly Epidemiol Rec 1993; 68:261–4.
15. Lumio J, Jakhola M, Vuento R, Haikala O, Eskola J. Diphtheria after visit
in Russia. Lancet 1993; 342:53–4.
16. Mathei C, Van Damme P, Bruynseels P, Goossens H, Vranckx R, Meheus
A. Diphtheria immunity in Flanders. Eur J Clin Microbiol Infect Dis
1997; 16:631–6.
17. Aggerbeck H, Fenger C, Heron I. Booster vaccination against diphtheria
and tetanus in man. Comparison of calcium phosphate and aluminium
hydroxide as adjuvants. II. Vaccine 1995; 13:1366–74.
18. Klouche M, Luhmann D, Kirchner H. Low prevalence of diphtheria anti-
S248
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
Galazka
toxin in children and adults in Northern Germany. Eur J Clin Microbiol
Infect Dis 1995; 14:682–5.
Wirz M, Puccinelli M, Mele C, Gentili C. Immunity to diphtheria in the
4–70 year age group in Italy. Vaccine 1995; 13:771–3.
Rix BA, Zhobakas A, Wachmann CH, Bakasenas V, Ronne T. Immunity
from diphtheria, tetanus, poliomyelitis, measles, mumps and rubella
among adults in Lithuania. Scand J Infect Dis 1994; 26:459–67.
Bjorkholm B, Wahl M, Granstrom M, Hagberg B. Immune status and
booster effects of low doses of diphtheria toxoid in Swedish medical personnel. Scand J Infect Dis 1989; 21:429–34.
Miller E, Rush M. Immunity to diphtheria in adults in England [letter].
BMJ 1994; 308:598.
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.
Comodo N, Bonanni P, Lo Nostro A, Tiocone E, Mannelli F, Tomei A. low
prevalence of diphtheria immunity in the population of Florence, Italy.
Eur J Epidemiol 1996; 12:251–5.
Galazka AM, Robertson SE. Diphtheria: changing patterns in the developing
world and the industrialized world. Eur J Epidemiol 1995; 11:107–17.
Zakrzewska A, Galazka A, Rymkiewicz D. Changes in age-specific immunity
to diphtheria in Poland in the past 40 years. EuroSurveillance 1997; 2:
64–7.
Immunisation procedures, IV ed. Australia: National Health and Medical
Research Council, 1991.
Canadian Immunization Guide. 3rd ed. Canada: Minister of National Health
and Welfare, 1989.
Levy-Bruhl D, Pebody R, Velhhuijzen I, Valenciano M, Osborne K. ESEN:
a comparison of vaccination programmes. Part one: diphtheria. EuroSurveillance 1998; 3:93–6.
Marth E. Booster policy for adults. Biologicals 1997; 25:199–203.
JID 2000;181 (Suppl 1)
31. Advisory Committee on Immunization Practices. Diphtheria, tetanus, and
pertussis recommendations for vaccine use and other preventive measures.
MMWR Morb Mortal Wkly Rep 1991; 40:1–28.
32. Galazka A. The rationale for the replacement of tetanus toxoid (TT) with
the tetanus-diphtheria vaccine (Td). In: XV meeting of the European
Advisory Group on the Expanded Programme on Immunization (Warsaw,
9–10 November 1998). Copenhagen: WHO Regional Office for Europe;
CMDS 01 01 02/25.
33. Simonsen O, Klaerke M, Klaerke A, et al. Revaccination of adults against
diphtheria. II: combined diphtheria and tetanus revaccination with different doses of diphtheria toxoid 20 years after primary immunization.
Acta Pathol Microbiol Immunol Scand [C] 1986; 94:219–25.
34. Balestra DJ, Littenberg B. Should adult tetanus immunization be given as
a single vaccination at age 65? A cost-effectiveness analysis. J Gen Intern
Med 1993; 8:405–12.
35. LaForce M. Routine tetanus immunizations for adults. Once is enough. J
Gen Intern Med 1993; 8:459–60.
36. Richardson JP. Tetanus immunization: concerns about the elderly and about
diphtheria reemergence. J Gen Intern Med 1994; 9:117; discussion 118.
37. Sutter RW, Strikas RA, Hadler SC, Fedson DS, Katz SL. Tetanus immunization: concerns about the elderly and about diphtheria reemergence. J
Gen Intern Med 1994; 9:117–8.
38. World Health Organization. Children’s Vaccine Initiative and Global Programme for Vaccines and Immunization. Report of the meeting of the
Scientific Advisory Group of Experts (SAGE) (Geneva, 9–11 June 1998).
Geneva: WHO; WHO/GPV/98.06.
39. Galazka AM, Robertson SE. Immunization against diphtheria with special
emphasis on immunization of adults. Vaccine 1996; 14:845–57.
40. Youwang Y, Jioanming D, Yong X, Pong Z. Epidemiological features of an
outbreak of diphtheria and its control with diphtheria toxoid immunization. Int J Epidemiol 1992; 21:807–11.