Epidemic Diphtheria Research Articles

Epidemiology of Diphtheria in the 1990s

Introduction Respiratory diphtheria, a severe systemic illness caused by toxigenic strains of Corynebacterium diphtheriae, was one of the most common causes of death among children in the pre-vaccine era. Diphtheria toxoid vaccine was developed in the 1920s. Widespread immunization led to the virtual elimination of diphtheria in developed countries by the 1960s and to a marked reduction of diphtheria cases in developing countries in the 1980s. The control of diphtheria has resulted in a larger proportion of adults lacking immunity as a result of failure to vaccinate or waning immunity among the vaccinated in the absence of exposure to infection. In the early 1990s, epidemic diphtheria re-emerged in the Newly Independent States (NIS) of the former Soviet Union after 30 years of control and caused thousands of deaths, primarily among adults. This paper briefly reviews the epidemiology of diphtheria in developed and developing countries, focusing on the 1990s, and comments on recent laboratory developments.

Rapid Identification of Corynebacterium diphtheriae Clonal Group Associated with Diphtheria Epidemic, Russian Federation

Rapid Identification of Corynebacterium diphtheriae Clonal Group Associated with Diphtheria Epidemic, Russian Federation

Rapid identification of Corynebacterium diphtheriae clonal group associated with diphtheria epidemic, Russian Federation.

We used 199 Corynebacterium diphtheriae isolated from 1995 to 1997 in Russia to evaluate the ability of random amplified polymorphic DNA (RAPD) to identify the unique clonal group that emerged there in 1990. Our data show that RAPD can reliably, reproducibly, and rapidly screen a large number of strains to identify the epidemic clonal group.

Impact of a vaccination campaign on adult immunity to diphtheria

Objectives: to raise the level of immunity to diphtheria in the adult population of Stockholm by a vaccination campaign. The rationale behind the campaign, conducted during 1995–1996, was the re-emergence of epidemic diphtheria in the countries of the former Soviet Union and earlier surveys of immunity to diphtheria showing low levels of protection in adults. Design and main outcome measures: the impact of the vaccination campaign was measured by recording the age and sex of vaccinees, the type and number of vaccine doses given and any side-effects. The effect on immunity was evaluated in 1998–1999 by measuring the neutralising antibodies in blood samples from 1863 inhabitants, chosen by random stratified sampling. Vaccines and vaccinations: three doses of diphtheria (D) or diphtheria-tetanus (DT) vaccine were given to those without documented previous vaccination; others received a booster dose. The DT vaccine, with the D component purified before toxoiding, contained 15 Lf of D and 7.5 Lf of T per ml, and was given in 0.5 ml doses for the two priming doses and 0.25 ml as booster. Results: 184 969 doses of D or DT vaccine were given to 99 939 individuals. Of the vaccinees, 65% were 50 years of age or older and 60% were women. The highest rates of reported local reactions were 1.8–5.4% and of systemic reactions, such as fever, 0.2–0.8%. The campaign resulted in a significant increase in antitoxin concentrations in the age cohorts targeted, and especially in women, less well protected than men. Conclusions: a vaccination campaign, targeting the adult part of a population, can result in a major improvement in immunity to diphtheria with only a few and minor side-effects with a DT vaccine where the D component was purified prior to toxoiding. Extending national immunisation programmes to include adults would, however, seem preferable.

Diphtheria Boosters for Adults May Not Be Effective

Ongoing diphtheria epidemics in Eastern Europe, and a worldwide increase in diphtheria cases, have raised concerns about optimal approaches to adult

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.

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.

Epidemic Diphtheria in the Newly Independent States of the Former Soviet Union: Implications for Diphtheria Control in the United States

The re-emergence of diphtheria in the Newly Independent States of the former Soviet Union in the 1990s raised global awareness of the potential for resurgent disease in countries with long-standing immunization programs. In the United States, the large population of susceptible adults and the possibility of a reintroduction of toxigenic strains of diphtheria create a setting in which diphtheria could spread. In addition, at least one focus of continued circulation of endemic toxigenic Corynebacterium diphtheriae has been identified. Few physicians now have expertise in the diagnosis and treatment of persons with diphtheria, and laboratory capacity is lacking throughout the country. These concerns highlight the importance of maintaining high levels of age-appropriate diphtheria toxoid vaccination, surveillance, accessible and reliable laboratory testing, and training of health care providers. Although the risk of resurgence of diphtheria in the United States is low, public health authorities must ensure that the capacity to recognize, diagnose, and control diphtheria is maintained.

Successful control of epidemic diphtheria in the states of the Former Union of Soviet Socialist Republics: lessons learned.

Epidemic diphtheria reemerged in the Russian Federation in 1990 and spread to all Newly Independent States (NIS) and Baltic States by the end of 1994. Factors contributing to the epidemic included increased susceptibility of both children and adults, socioeconomic instability, population movement, deteriorating health infrastructure, initial shortages of vaccine, and delays in implementing control measures. In 1995, aggressive control strategies were implemented, and since then, all affected countries have reported decreases of diphtheria; however, continued efforts by national health authorities and international assistance are still needed. The legacy of this epidemic includes a reexamination of the global diphtheria control strategy, new laboratory techniques for diphtheria diagnosis and analysis, and a model for future public health emergencies in the successful collaboration of multiple international partners. The reemergence of diphtheria warns of an immediate threat of other epidemics in the NIS and Baltic States and a longer-term potential for the reemergence of vaccine-preventable diseases elsewhere. Continued investment in improved vaccines, control strategies, training, and laboratory techniques is needed.

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 </=14 years old. The highest CFR occurred among adults 40-49 years of age (CFR=19%) and children 5-9 years of age (CFR=16%). Children who did not have the complete primary vaccination series with diphtheria toxoid and adults 40-49 years of age were the 2 groups at highest risk. Being a rural resident and having a long interval (>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.

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.

The changing epidemiology of diphtheria in the vaccine era.

The epidemic of diphtheria in the Newly Independent States (NIS) of the former Soviet Union has drawn attention to our incomplete understanding of the epidemiology of diphtheria. Many unanswered questions remain concerning the reasons for a resurgence of diphtheria and for the shift in the age of patients and concerning the mechanisms for acquisition of immunity in adults through natural infection under unfavorable living conditions. Other unanswered questions relate to the precise role of socioeconomic factors and hygiene conditions in the initiation, buildup, and spread of the epidemic. Important characteristics of the NIS epidemic can be used to help predict the spread of future diphtheria epidemics. These characteristics include a high proportion of infected adults, a progressive spread of disease from urban centers to rural areas, and transition from initial amplification of disease in groups with high rates of close contacts in focalized, well-distinguished outbreaks to a more generalized epidemic.

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.

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.

Assessment of vaccination coverage among adults 30-49 years of age following a mass diphtheria vaccination campaign: Ukraine, April 1995.

Ukraine has been experiencing epidemic diphtheria since 1991. In efforts to control this epidemic, a mass vaccination campaign was held in April 1995. Persons not vaccinated in the previous 3 years were considered eligible for vaccination with tetanus-diphtheria toxoids (Td). Two cluster sample surveys were conducted to determine vaccination coverage achieved. In the urban and rural survey areas, respectively, 628 and 618 persons 30-49 years of age were interviewed. Fifty-nine percent of urban and 58% of rural participants were eligible for vaccination. During the vaccination campaign, 58% (95% confidence interval [95% CI], 47.1-69.2) of eligible persons received Td in the urban area, compared with 92% (95% CI, 89.2-95.3) in the rural area. Apparent barriers to vaccination included misconceptions about the safety, efficacy, and need for booster doses of Td. Future vaccination campaigns should include targeted information and education messages. Mass vaccination campaigns can be successful in vaccinating large numbers of adults; however, in urban areas, additional efforts may be required to achieve levels of coverage adequate to confer herd immunity and interrupt the diphtheria epidemic.

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.

Control of Epidemic Diphtheria in the Newly Independent States of the Former Soviet Union, 1990–1998

Control of Epidemic Diphtheria in the Newly Independent States of the Former Soviet Union, 1990–1998

Epidemiology of epidemic diphtheria in three regions, Russia, 1994-1996.

A massive diphtheria epidemic which began in the former Soviet Union in 1990 is the first large-scale diphtheria epidemic in developed countries in more than 30 years and has primarily affected adults. In response, health authorities attempted to maximize vaccination for children and conducted an unprecedented campaign to vaccinate adults. We analyzed diphtheria surveillance data (case report forms and diphtheria vaccine coverage data) from three Russian regions from January 1994 to December 1996 and estimated vaccine effectiveness by the screening method. We reviewed records from 2243 (97.2%) of 2307 reported cases. The highest cumulative incidence in the period was among children aged 5 to 9 years (106 cases per 100,000 population); adults aged 40-49 years had the highest adult incidence for disease (88 cases per 100,000) and the highest incidence of any age group of clinically severe disease (29 cases per 100,000) and death (5.1 deaths per 100,000). The incidence among women aged 2049 years (82 per 100,000 women) was higher than among men (47 per 100,000, p<0.01). The annual incidence decreased from 25.2 cases per 100,000 population in 1994 to 9.4 cases per 100,000 in 1996. The decrease occurred as adult coverage increased from an estimated 25-30% in December 1992 to 88% in December 1995. Vaccine effectiveness was high among both children and adults. The Russian diphtheria epidemic primarily affected adults, especially women; this pattern is likely representative of diphtheria epidemics in immunized populations. Raising childhood immunization coverage and mass adult vaccination was effective in controlling the Russian epidemic. An improved understanding of the current epidemiology of diphtheria will be useful to design public health responses to prevent or control modern epidemics.

Heterogeneity of diphtheria toxin gene, tox, and its regulatory element, dtxR, in Corynebacterium diphtheriae strains causing epidemic diphtheria in Russia and Ukraine.

Diphtheria toxin (tox) and its regulatory element (dtxR) from 72 Corynebacterium diphtheriae strains isolated in Russia and Ukraine before and during the current diphtheria epidemic were studied by PCR-single-strand conformation polymorphism analysis (PCR-SSCP). Twelve sets of primers were constructed (eight for tox and four for dtxR), and three regions within tox and all four regions of dtxR showed significant variations in the number and/or sizes of the amplicons. Two to four different SSCP patterns were identified in each of the variable regions; subsequently, tox and dtxR could be classified into 6 and 12 different types, respectively. The great majority of epidemic strains from both Russia and Ukraine had tox types 3 and 4, and only in a single preepidemic strain isolated in Russia were all eight tox regions identical to those of C. diphtheriae Park-Williams No. 8 (tox type 1). Epidemic strains from Ukraine can easily be identified by dtxR type 5, while the majority of the Russian epidemic strains have dtxR of types 2 and 8. No differences in the tox regions between mitis and gravis biotype strains were observed. However, dtxR types 2, 5, and 8 were identified only in the gravis biotype, and dtxR type 1 was characteristic for the mitis biotype strains. PCR-SSCP is a simple and rapid method for the identification of variable tox and dtxR regions that allows for the clear association of tox and dtxR types with strains of distinct temporal and/or geographic origins.

Diphtheria Epidemic — New Independent States of the Former Soviet Union, 1990–1994

Although diphtheria was controlled for approximately 30 years after the institution of childhood vaccination with diphtheria toxoid in the late 1950s, epidemic diphtheria has reemerged in the New Independent States (NIS) of the former Soviet Union (1,2) (Figures 1 and 2). The epidemic began in 1990 in the Russian Federation and spread to Ukraine in 1991 and, during 1993-1994, to 12 of the 13 remaining NIS. In most affected countries, the incidence rate of reported diphtheria has increased twofold to 10-fold each year. This report summarizes data provided to the World Health Organization (WHO) about diphtheria in the NIS during 1989-1994.*