Diphtheria epidemic in the Republic of Uzbekistan, 1993-1996

The Republic of Uzbekistan, like the other Newly Independent States in the 1990s, experienced epidemic diphtheria during the 1990s. The outbreak in Uzbekistan began in 1993 in southern regions that bordered areas of Tajikistan that were experiencing a very intense diphtheria epidemic. However, the Uzbek epidemic rapidly spread and threatened to involve the entire country. From 1993-1996, 1169 cases of diphtheria were reported, compared with 58 in 1990-1992. Unvaccinated or only partially vaccinated cases were more likely to have clinically severe forms of diphtheria than those who were fully vaccinated. Strong epidemiologic links with the Tajik diphtheria epidemic and the predominance of mitis biotype strains of Corynebacterium diphtheriae in Uzbekistan make it likely that the Uzbek outbreak arose independently of the predominantly biotype gravis epidemic that began in Russia. The epidemic appeared to be due to low population immunity and the large-scale reintroduction of toxigenic strains of C. diphtheriae. Several mass vaccination campaigns and general enhancement of routine immunization procedures led to control of the epidemic in 1996.     

Diphtheria surveillance and control in the Former Soviet Union and the Newly Independent States

The Newly Independent States (NIS) inherited a common approach to diphtheria control from the Soviet Union and maintained a centralized system of surveillance and control managed by Soviet-trained epidemiologists with a shared professional culture. This system had controlled a diphtheria resurgence in the 1980s. In response to the epidemic of the 1990s, NIS health authorities responded with a set of control measures based on the Soviet-era experience. These measures included intensified childhood vaccination, aggressive case investigation, widespread diphtheria screening in institutions, and vaccination of adults in high-risk occupation groups. These measures proved insufficient due to high levels of susceptibility among adults, excessive contraindications to childhood vaccination, and insufficient resources in many countries. After these initial delays in implementing effective measures in some countries, most of the NIS health authorities rapidly and successfully implemented mass immunization of the population against diphtheria once the strategy was adopted and sufficient vaccine was available.     

Diphtheria toxoid vaccine effectiveness: A case-control study in Russia

Prior to the completion of this and other studies, low effectiveness of diphtheria toxoid-containing vaccine was suspected to be a major contributing factor to the diphtheria epidemic that began in the Russian Federation in 1990. A vaccine effectiveness study was done in Moscow by enrolling physician-diagnosed cases and 10 control subjects per case. Controls were matched to cases by age (+/-3 months) and clinic registration. Vaccination history was abstracted from a standardized form for case-patients and from clinic vaccination records for control subjects. Two hundred seventeen case-patients and 2169 matched controls were included in the study. Most controls (92%) had received three or more doses of a diphtheria toxoid vaccine, compared with 72% of case-patients. The vaccine effectiveness for three or more doses was 97% (95% confidence interval: 94.3-98.4). Low vaccine effectiveness was not a contributing factor to the diphtheria epidemic in the Russian Federation. To control and prevent diphtheria epidemics, it is necessary to achieve and maintain high vaccination coverage with three or more doses of diphtheria toxoid among adults and children.     

Diphtheria in Estonia, 1991-1996

Clinical diphtheria reappeared in Estonia in 1991. Between 1991 and 1996, 61 cases and 5 deaths occurred; 19 cases were among children 5-9 years of age, and 11 were among persons 40-49 years of age. From 1993-1995, vaccine supplies donated by Finland were used in vaccination programs. In 1995, the International Federation of Red Cross and Red Crescent Societies and the Estonian Red Cross launched a mass vaccination campaign targeting the adult population. By the end of 1997, it was estimated that 46% of adults had received at least one dose of vaccine. Although the vaccination campaigns did not target the pediatric population, vaccination coverage in school-aged children remained high due to continuing routine vaccination programs. The reappearance and epidemic of clinical diphtheria cases and the mass vaccination campaign efforts demonstrated that preventive measures are important and must be maintained in order to keep diphtheria under control.     

Epidemic diphtheria in Belarus, 1992-1997

In 1990, epidemic diphtheria reemerged in Russia and spread to Belarus in 1992, when 66 cases were reported. Diphtheria cases doubled each year in 1993 and 1994 and peaked in 1995, when 322 cases were reported. Intensified routine immunization of young children and mass vaccination of older children and selected groups of adults were conducted in 1995 and were followed by mass vaccination campaigns targeting all adults in 1996. By the end of 1996, full immunization of >95% of children and coverage of>87% of adults with >/=1 dose resulted in a rapid decline in diphtheria cases. In 1998, only 36 cases of diphtheria were reported. More than 70% of the 965 cases and 26 fatalities reported during 1990-1998 occurred among persons >14 years of age. High levels of immunity among the entire population are needed for rapid control of diphtheria epidemics in the vaccine era.     

Epidemic diphtheria in the 1990s: Azerbaijan

The diphtheria epidemic in the former Soviet Union reached Azerbaijan in 1991, when 66 cases of diphtheria were reported, a number that compared with 4 cases in 1990. From 1990-1996, 2182 cases of diphtheria and 286 diphtheria fatalities (case fatality rate: 13.1%) were reported in Azerbaijan, primarily among persons 5-39 years of age. Almost 45% of cases and 61% of deaths occurred among children 5-14 years of age. The high burden of severe disease among children and young adults suggested a different pattern of preexisting immunity against diphtheria in the Azerbaijani population than was observed in the concurrent diphtheria epidemic in Russia. Because resources were limited in Azerbaijan, mass immunization of the population was carried out in stages, focusing initially on school-aged children. Mass immunization campaigns targeting children were moderately successful in stabilizing the epidemic; mass immunization campaigns targeting both adults and children were eventually needed to fully stop the epidemic.     

Diphtheria in Lithuania, 1986-1996

Diphtheria reappeared in Lithuania in 1986 and rose to epidemic levels by 1992. Between 1991 and 1996, 110 cases of diphtheria were registered, with an incidence of 0.03-1.15/100,000 population. Most cases (84%) and all 17 deaths occurred among persons >/=15 years, most of whom had never been vaccinated. Persons 40-49 years old had the highest average annual age-specific morbidity (1.70/100,000) and mortality (0.53/100,000) rates. Low levels of immunity among individuals 40-49 years old and migration to epidemic areas in Russia and Belarus contributed to the epidemic's occurrence. Between 1991 and 1995, toxigenic Corynebacterium diphtheriae strains were isolated from 84 of all registered patients (76%), and nontoxigenic strains were isolated from 13 (12%). By 1996, two mass vaccination campaigns, which provided one dose of vaccine to individuals 25-30 years old and three doses of vaccine to persons 31-60 years old, helped reduce the number of cases. The first campaign achieved 69% coverage; the second achieved 48% coverage.     

Diphtheria in Thailand in the 1990s

Diphtheria remains endemic in developing countries, but there are limited published data on the subject. Thailand's diphtheria surveillance data are relatively complete and may give a fuller picture of the situation in similar countries. After routine immunization began in 1977, the incidence of reported diphtheria decreased by >98% to <0.1 case per 100,000 persons annually in the 1990s. Despite infant immunization coverage of >90%, diphtheria cases were reported throughout the 1990s, primarily among children <15 years old. Outbreaks were linked to both persistent endemic circulation and to importation of toxigenic Corynebacterium diphtheriae; suboptimal immunization coverage in minority and disadvantaged groups contributed. A serologic survey found 25% of adults 20-39 years old and 14% of adolescents 10-19 years old lacked immunity to diphtheria; these data indicate an accumulation of susceptible adolescents and adults. Diphtheria remains a threat in Thailand; improvements in diphtheria control will depend on improving childhood immunization coverage in Thailand and the surrounding region.     

Diphtheria in Latvia, 1986-1996

After nearly two decades without a diphtheria case in Latvia, the disease reappeared in 1986. From 1990 to 1996, case counts were highest among adults 40-49 years of age, school-aged children, and adolescents. Nonetheless, the average annualized incidence of disease was highest among infants and preschoolers. In August 1995, mass vaccination efforts began to provide adults 25-60 years of age with at least one dose of vaccine. By the end of the year, a 77% coverage rate was achieved, resulting in a decrease of reported diphtheria cases by 1996. From February to September 1997, special outreach efforts were focused on hard-to-reach populations; as a result, by June 1997, 55% of adults had received three doses of vaccine. While decreases in the incidence of and morbidity from diphtheria have occurred, additional efforts still need to be concentrated on improving vaccination coverage in adults and children <2 years of age and in reducing mortality from diphtheria.     

Ukraine, 1992: first assessment of diphtheria vaccine effectiveness during the recent resurgence of diphtheria in the Former Soviet Union

A case-control study in Ukraine provided the first data on the field effectiveness of Russian-produced vaccine during the 1990 diphtheria resurgence in the former Soviet Union. For each of 262 diphtheria cases <15 years of age who were reported from January through October 1992, 2 controls, matched by age and clinic, were selected. The effectiveness of three doses of diphtheria vaccine was 98.2% (95% confidence interval: 90.3-99.9). Among controls, 84% had received three or more vaccinations by 2 years of age. These results suggest that the following five hypothesized causes of the outbreak appeared unlikely: appearance of a new "mutant" diphtheria strain, low potency of the Russian-produced diphtheria vaccine, inadequate cold chain, poor host immunogenicity due to radiation exposure from Chernobyl, and low routine childhood vaccination coverage. It is concluded that initial priority for scarce resources for controlling this outbreak should be placed on vaccination of persons susceptible to diphtheria (e.g., adults) rather than revaccination of children.     

Epidemic diphtheria in the Kyrgyz Republic, 1994-1998

The Kyrgyz Republic experienced a widespread diphtheria epidemic during 1994-1998. National diphtheria surveillance and vaccination coverage information were used to describe the course of the epidemic. The epidemic began in August 1994, reached a peak in 1995 with 704 cases (incidence rate: 15.4/100,000 population) and 30 deaths, and declined to an incidence rate of 4.0/100,000 during the first 8 months of 1998. Age-specific incidence was highest in 1995 among persons 15-19 and 20-29 years old. Three rounds of mass vaccination with tetanus and diphtheria toxoids for adult use (Td) were conducted; reported coverage was 69% in 1995 and >95% in 1996 and 1997. Reported routine vaccination coverage with three doses of diphtheria toxoid by age 12 months increased from 62% in 1989 to 98% in 1997. Mass vaccination of the adult population with Td and improvements in childhood vaccination coverage played a major role in controlling the epidemic.     

Epidemic diphtheria in Ukraine, 1991-1997

In 1991, Ukraine experienced a return of epidemic diphtheria after decades of control that had resulted in <40 sporadic cases reported every year. Increased incidence was first recorded in Kiev, Lviv, and Odessa. By 1993, the epidemic had spread to >50% of the oblasts (provinces) in the country, and by 1995, all regions were affected. In 1995, at the peak of the epidemic, >5,000 cases and >200 deaths were reported. As in Russia, >80% of these cases were diagnosed in persons 16-59 years old. In 1993, the government of Ukraine initiated a program of increased immunization among children and at-risk adults, and by 1995, a mass immunization strategy was adopted in an effort to arrest the epidemic, which was increasing exponentially. In 1996, the number of cases started to decrease, and data from 1998 indicate that the downward trend has continued. It is likely that the diphtheria epidemic in Ukraine started among children, who had been left vulnerable due to inadequate childhood immunizations, and then quickly spread to inadequately protected adults.     

Contraindications to vaccination in the Russian Federation

Failure to achieve high levels of immunity among children contributed to the epidemic of diphtheria that occurred in the Russian Federation during the 1990s. A major factor in this failure was the extensive list of contraindications to vaccination that was in use throughout the countries of the former Soviet Union. In 1980, the Ministry of Health (MOH) of the Soviet Union adopted an extensive list of contraindications for use of the diphtheria-tetanus toxoids-pertussis (DTP) vaccine. In 1994, the MOH of the Russian Federation revised the list of contraindications to vaccination to be largely in accord with World Health Organization recommendations. Since then, age-appropriate vaccination coverage has increased markedly: In 1996, DTP3 coverage among children 12 months of age had increased to 87% from 60% in 1990.     

Epidemic diphtheria in the Republic of Georgia, 1993-1996: risk factors for fatal outcome among hospitalized patients

Epidemic diphtheria reemerged in the republic of Georgia in November 1993. To identify risk factors for fatal outcomes, clinical and epidemiologic data on all hospitalized diphtheria patients were examined. Medical charts of patients from 1993-1995 were reviewed. A total of 659 cases and 68 deaths were identified (case fatality rate [CFR] = 10.3%). Fifty-two percent of all cases and 68% of deaths were in children 3 days) between onset of symptoms to antitoxin treatment were significantly associated with fatal outcomes. Immunization of children and 40- to 49-year-old adults was required to rapidly control the epidemic.     

Impact of the meningococcal C conjugate vaccine in Spain: an epidemiological and microbiological decision

The new meningococcal C conjugate vaccine became available in Spain and was included in the infant vaccination schedule in 2000. A catch-up campaign was carried out in children under six years of age. As a consequence, the incidence of meningococcal disease caused by serogroup C has fallen sharply during the last three epidemiological years in Spain. The risk of contracting serogroup C disease in 2002/2003 fell by 58% when compared with the season before the conjugate vaccine was introduced. There was also an important decrease in mortality. Three deaths due to serogroup C occurred in the age groups targeted for vaccination in 2002/2003, compared with 30 deaths in the same age groups in the season before the launch of the vaccine campaign. In the catch-up campaign the vaccine coverage reached values above 92%. For the 2001, 2002 and 2003 routine childhood immunisation programme coverage values ranged from 90% to 95%. During the past three years a total of 111 cases of serogroup C disease have been reported in patients in the vaccine target group. Most of the vaccination failures occurred during the epidemiological year 2002/2003. Eight (53%) vaccine failures occurred in children who had been routinely immunised in infancy, and could be related to a lost of protection with time since vaccination. The isolation of several B:2a:P1.5 strains (ST-11 lineage) is noteworthy. These may have their origin in C:2a:P1.5 strains which, after undergoing genetic recombination at the capsular operon level, express serogroup B. These strains could have relevant epidemic potential.     

Report on the Sixth International Meeting of the European Laboratory Working Group on Diphtheria,Brussels, Belgium

In addition to the Eastern European resurgence of diphtheria during the last decade, there has also been an emergence of infections caused by non-toxigenic Corynebacterium diphtheriae and non-toxigenic, toxin gene bearing C. diphtheriae. Given that these strains may manifest as symptomatic infections of differing degrees of severity, their clinical and epidemiological significance need to be assessed. The persistence of toxigenic and non-toxigenic C. diphtheriae in circulation, together with genotypic and biotype variability means that innovative measures to vaccinate populations are pertinent. The most effective method of protecting the currently most vulnerable population group (adults) is to implement a booster dose of vaccine amongst the adult populations. Furthermore, in combination with an efficient surveillance system, effective antibiotic prophylaxis and an up-to-date vaccination programme, serological studies needs to be maintained to monitor the immunity status of the population.     

How many doses of diphtheria toxoid are required for protection in adults? Results of a case-control study among 40- to 49-year-old adults in the Russian Federation

During the Russian diphtheria epidemic of the 1990s, adults had an unexpectedly high rate of disease. A retrospective, matched case-control study was done to measure the effectiveness of one, two, or three or more doses of diphtheria toxoid against diphtheria among 40- to 49-year-old Russians. Thirty-nine diphtheria case-patients and 117 controls were studied. Previous vaccinations were included if one dose was received within the previous 10 years. Five cases (13%) and 33 controls (28%) had received three or more doses of vaccine. The matched odds ratio was 0.3 (95% confidence interval, 0.1-0.9) for three or more doses compared with no doses, which was a vaccine effectiveness of 70% (95% confidence interval, 10-90). A trend existed toward milder disease with increasing doses (chi2 test for trend, P=.02). The results suggest that Russian adults, who were unlikely to have acquired immunity to diphtheria through immunization or natural infection, required at least three doses of diphtheria toxoid for reliable protection against disease.     

Diphtheria epidemic in the Republic of Georgia, 1993-1997

Epidemic diphtheria reemerged in the republic of Georgia in 1993. From 1993 to 1997, 1405 cases were reported (28 in 1993, 312 in 1994, 429 in 1995, 348 in 1996, and 288 in 1997), with a cumulative incidence of 25.8/100,000 and a case fatality ratio of 9.5%. During 1993-1997, 53% of the diphtheria cases occurred among persons >/=15 years of age. Unvaccinated patients were more likely to have toxic forms (relative risk=2.24; 95% confidence interval=1.69-2.96) or to die of diphtheria (relative risk=2.24; 95% confidence interval=1. 36-3.68) than those who had received at least one dose of diphtheria toxoid. Improvement in routine childhood vaccination coverage and implementation of mass adult vaccination campaigns have been critical to bringing the epidemic under control. By mid-1998, the overall diphtheria situation in Georgia appeared to have been controlled. Only 53 cases were reported from January to June 1998, representing a 64% decrease from the 148 cases during the corresponding period in 1997.     

Implications of the diphtheria epidemic in the Former Soviet Union for immunization programs

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.     

Molecular epidemiology of diphtheria

Molecular subtyping of Corynebacterium diphtheriae identified significant genetic diversity within the species and led to the identification of a unique clonal group that emerged in Russia in 1990 at the beginning of the current epidemic. Strains of this group belong to a distinct electrophoretic type complex and are of ribotypes D1 and D4. Identification of the group allowed for precise monitoring of the epidemic's progression and for rapid detection of cases imported to other countries. The evolution of this clonal group was monitored, and changes were identified. Molecular analysis revealed that no amino acid substitutions have occurred in the diphtheria toxin gene of the epidemic clone strains, reaffirming the use of the current vaccine as the single most effective preventive measure. Application of molecular subtyping methods and continuous monitoring of the spread of these clones has made it possible to distinguish rapidly between epidemic, endemic, and imported cases, allowing for implementation of timely and adequate preventive measures and providing reassurance that no secondary spread resulted from importations.