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PubMed1997

Clinical and molecular study of Corynebacterium diphtheriae systemic infections in France. Coryne Study Group.

Diphtheria is a disease with a long history that almost completely disappeared from developed countries. In addition, until 1987, systemic infections involving Corynebacterium diphtheriae were rare. However, in 1990, an epidemic occurred in Russia. These two circumstances have provided the stimulus to gain insight into the situation in France. In fact, between 1987 and 1993, a total of 59 C. diphtheriae strains were isolated. Epidemiological data were collected for patients from whom 40 strains were isolated from normally sterile sites, including 34 from blood cultures, and half of the bacteremic patients developed endocarditis. Osteoarticular involvement was noted in 11 of these 40 patients, including 5 bacteremic patients. The fatality rate following bacteremia was 36%, despite specific antibiotic treatment (beta-lactams and aminoglycosides). The mean age of the participants was 38 years, with half of the patients subsisting under low socioeconomic conditions and suffering from homelessness or alcoholism. Apparently, the skin turned out to be the major route of transmission in this reemerging disease. Eighty-eight percent of the isolates belonged to the C. diphtheriae biotype mitis. These were found predominantly in the Paris area, and most were of the same ribotype. Those isolates originating from the overseas territories (Guyana and New Caledonia) belonged to C. diphtheriae biotype gravis. No strains were positive for the tox gene by PCR. This study attests to the persistent circulation in France of C. diphtheriae in the form of systemic infections. The matter is especially significant since these strains are nontoxigenic and are of a unique ribotype. The strains are, however, sensitive to most antibiotics, although 20% are rifampin resistant.

Adolescent↗
PubMed1998

Comparison of phenotypic and genotypic methods for detection of diphtheria toxin among isolates of pathogenic corynebacteria.

We have compared molecular, immunochemical, and cytotoxic assays for the detection of diphtheria toxin from 55 isolates of Corynebacterium diphtheriae and Corynebacterium ulcerans originally isolated in five different countries. The suitabilities and accuracies of these assays for the laboratory diagnosis of diphtheria were compared and evaluated against the "gold standard" in vivo methods. The in vivo and Vero cell cytotoxicity assays were accurate in their abilities to detect diphtheria toxin but were time-consuming; however, the cytotoxicity assay is a suitable in vitro alternative to the in vivo virulence test. There was complete concordance between all the phenotypic methods. Genotypic tests based upon PCR were rapid; however, PCR must be used with caution because some isolates of C. diphtheriae possessed toxin genes but failed to express a biologically active toxin. Therefore, phenotypic confirmation of toxigenicity for the microbiological diagnosis of diphtheria is recommended.

Animals↗
PubMed1983

Immunisation of adults during an outbreak of diphtheria.

In an outbreak of infection due to Corynebacterium diphtheriae in a hospital for mentally subnormal adults sera from 211 members of staff were screened for diphtheria antitoxin titres. Of these, 79 (37%) required immunisation, and a low dose preparation (1 LfU of diphtheria and 10 LfU tetanus toxoids) was offered. Of the 64 subjects who accepted a single immunisation and were subsequently retested, seroconversion to diphtheria toxoid occurred in 45 (70%), the rate being highest in younger adults. Seroconversion to tetanus toxoid occurred in 59% of subjects. Local reactions to the single dose were reported by 29 (43%) subjects, and nine (13%) experienced moderately severe local reactions and systemic symptoms. We conclude that adults should not be vaccinated without previous screening for susceptibility to diphtheria; that neither previous immunisation nor age is reliable in predicting the need for vaccination; and that though a single booster dose of diphtheria toxoid is probably effective in adults under 45, two doses should be given to those in the older age group.

Adult↗
PubMed2005

[Immunity to diphtheria among adults older than 65 years].

BACKGROUND AND OBJECTIVE: To know the immune state against diphtheria through a survey, a consultation of the vaccination documents and a seroepidemiologic study of an old population. PATIENTS AND METHOD: The immunization status and the prevalence of antidiphtheria antibodies were determined in a representative sample (n = 231) of this population group (> 65 years). Concentrations of toxin antibodies were measured using a commercial ELISA kit. Samples with titres > 0.1 UI/ml were considered protective. RESULTS: In the vaccination documents we only found 19 old individuals vaccinated against tetanus-diphtheria. 47.1% had no protective titres. Geometric mean titres were 0.12 UI/ml. There was no statistically significant difference between the variables age and sex and the prevalence of antibodies. 84.4% of the 122 seropositives did not report having received diphtheria vaccine and neither had documents about the vaccination. CONCLUSION: There were almost no documents about diphtheria vaccination. Therefore, the serologic study is the only reliable way to know the immunity status against diphtheria in elderly people. Approximately 50% of this population need primary immunization. The rest of this group need to have completed antidiphtheria vaccination or a dose booster within a period of 2 years in order to guarantee protective antibody levels against diphtheria.

Aged↗
PubMed2003

Seventh International Meeting of the European Laboratory Working Group on Diphtheria - Vienna, June 2002.

The Seventh International Meeting of the European Laboratory Working Group on Diphtheria (ELWGD) was held in Vienna, Austria in June 2002 and brought together the microbiologists and epidemiologists responsible for diphtheria in many countries throughout the world. The ELWGD was formed in 1993 in response to the epidemics of diphtheria in Russia and the Newly Independent States (NIS) of the former Soviet Union (1,2). These epidemics, and others elsewhere, highlighted the importance of strengthening and maintaining both epidemiological surveillance and reliable laboratory screening. Since December 2001, these areas have been progressed and strengthened by European Commission (EC) funding to undertake a feasibility study for diphtheria surveillance amongst European Union (EU) member states and accession countries, and to establish a definitive and official European diphtheria surveillance network called DIPNET (EC DG SANCO Agreement No. S12.324473 (2001 CVG4-012)). This was the first international meeting of the ELWGD to be organised and funded under the auspice of the DIPNET (European Diphtheria Surveillance Network).

Adolescent↗
PubMedDate not supplied

[Variants in the immune response to revaccination with diphtheria anatoxin in adults].

The immunological effectiveness of the revaccination (made in two injections) of 488 adults aged 18-67 years with diphtheria-tetanus toxoid is discussed; the parallel study of the results of this revaccination was carried out in the diphtheria toxin neutralization test on Vero cells and in the passive hemagglutination (PHA) test. The specific features of the dynamics of the increase of diphtheria antitoxic antibodies, depending on the initial immunity level, the age and the sex of revaccinated persons, were determined. Among persons with the low level of circulating antibodies before revaccination four variants of immune response to the injection of diphtheria toxoid were registered: variant 1--rapid reaction like in secondary immune response (53.6%); variant 2--delayed but effective reaction like in primary immune response (27.3%); variant 3--slow weak response (6.5%); and variant 4--the absence of effective immune response to immunization made in 2-3 injections (12.6%). The immunological and neutralizing properties of diphtheria antitoxic antibodies in the process of immunization made in 2 injections were evaluated. Persons with abnormal immune response (variants 3 and 4) produced defective antibodies, displaying immunological activity in the PHA test, but in most cases unable to neutralize diphtheria toxin in vitro when tested on Vero cells.

Adolescent↗
PubMed1977

[Diphtheria epidemic in eastern Switzerland in 1974].

A diphtheria epidemic in the eastern part of Switzerland in 1974 and the measures which were taken for its management and eradication are described. In particular it is pointed out that at present diphtheria displays atypical clinical symptoms in Europe, a fact that renders the diagnosis very difficult in many cases. Therefore, it is important to perform a throat swab in every patient with suspected diphtheria; it is also necessary to explicitly require a search for C. diphtheriae. The early recognition and early treatment of diphtheria with penicillin or erythromycin is of the utmost importance in order to avoid neurological and cardiac complications. With regard to the management and eradication of a diphtheria epidemic, the most important measures are rapid antibiotic protection of all contacts and a widespread immunization of the population. Vaccination of adults with a DiTe vaccine containing a reduced amount of Di-toxoid is recommanded.

Adolescent↗
PubMed1983

[Results of conducting an epidemiological survey of diphtheria in 21 territories of the RSFSR].

As the result of epidemiological survey of diphtherial infection, carried out in conformity with the unified methodological recommendations in 21 regions of the RSFSR during 1980-1981, the expediency of such experiment was established. Immunity to diphtheria in children aged up to 14 years was high: children with negative Schick tests constituted 96.9-99.1%. No biological changes in Corynebacterium diphtheriae occurred during the term of observation. Toxigenic C. diphtheriae showed a high level of pathogenicity. The epidemiological survey contributed to a more thorough detection of diphtheria patients and carriers releasing toxigenic C. diphtheriae. The quality of clinical bacteriological diagnosis improved. In rare cases angina with the concomitant carriership of toxigenic C. diphtheriae could be diagnosed with the indispensable serological examination of the patients by Jensen's method.

Adolescent↗
PubMed2005

Combined tetanus, diphtheria, and 5-component pertussis vaccine for use in adolescents and adults.

CONTEXT: Increasing reports of pertussis among US adolescents, adults, and their infant contacts have stimulated vaccine development for older age groups. OBJECTIVE: To assess the immunogenicity and reactogenicity of a tetanus-diphtheria 5-component (pertussis toxoid, filamentous hemagglutinin, pertactin, and fimbriae types 2 and 3) acellular pertussis vaccine (Tdap) in adolescents and adults. DESIGN, SETTING, AND PARTICIPANTS: A prospective, randomized, modified double-blind, comparative trial was conducted in healthy adolescents and adults aged 11 through 64 years from August 2001 to August 2002 at 39 US clinical centers. INTERVENTIONS: A single 0.5-mL intramuscular dose of either Tdap or tetanus-diphtheria vaccine (Td). MAIN OUTCOME MEASURES: Antibody titers to diphtheria and tetanus toxoids for Tdap and Td were measured in sera collected from subsets of adolescents and adults, before and 28 days after vaccination. For pertussis antigens, titers in sera from Tdap vaccinees were assessed vs those from infants who received analogous pediatric diphtheria-tetanus-acellular pertussis vaccine (DTaP) in a previous efficacy trial. Safety was assessed via solicited local and systemic reactions for 14 days and adverse events for 6 months following vaccination. RESULTS: A total of 4480 participants were enrolled. For both Tdap and Td, more than 94% and nearly 100% of vaccinees had protective antibody concentrations of at least 0.1 IU/mL for diphtheria and tetanus, respectively. Geometric mean antibody titers to pertussis toxoid, filamentous hemagglutinin, pertactin, and fimbriae types 2 and 3 exceeded (by 2.1 to 5.4 times) levels in infants following immunization at 2, 4, and 6 months with DTaP. The incidence of solicited local and systemic reactions and adverse events was generally similar between the Tdap and Td groups. CONCLUSIONS: This Tdap vaccine elicited robust immune responses in adolescents and adults to pertussis, tetanus, and diphtheria antigens, while exhibiting an overall safety profile similar to that of a licensed Td vaccine. These data support the potential routine use of this Tdap vaccine in adolescents and adults.

Adolescent↗
PubMed1997

Bacterial tracheitis caused by Corynebacterium diphtheriae.

UNLABELLED: Diphtheria has become a rare disease in Germany. We report on an unimmunized 3.5-year-old German girl with a 7-day history of respiratory distress and fever, presenting a clinical picture mimicking typical bacterial tracheitis without pharyngeal and laryngeal manifestation. Diagnosis of diphtheria was not made until culture of tracheal secretions yielded growth of a toxigenic strain of Corynebacterium diphtheriae. The patient died from toxic cardiac failure despite treatment with diphtheria antitoxin. This is the second reported case of isolated bacterial tracheitis caused by Corynebacterium diphtheriae. CONCLUSION: The observation of a lethal course of diphtheric tracheitis emphasizes the paramount importance of immunization against diseases like diphtheria.

Bacteriological Techniques↗
PubMed1989

Combined estimation of tetanus and diphtheria antitoxin in human sera by the in vitro Toxin-Binding Inhibition (ToBI) test.

The use of the principle of inhibition of toxin binding to an antitoxin coated immunoassay plate as described in a previous paper for tetanus antitoxin titration, was adapted for the estimation of diphtheria antitoxin in human sera. With a few modifications, a Toxin-Binding Inhibition (ToBI) test was developed which could be used for a combined estimation of both tetanus and diphtheria antitoxin levels. The application of streptavidin-biotinylated peroxidase complex when using small serum samples (less than 50 microliters) is discussed. Antitoxin titres (both diphtheria and tetanus) of 0.002 IU ml-1 were detectable by the ToBI test, this being far below the level considered to be protective in man. Sera from 140 adults with different vaccination histories were titrated for both tetanus and diphtheria antitoxin. Good correlations were found between the estimates obtained by the ToBI test and those obtained by the toxin-neutralization (TN) test in mice (tetanus antitoxin) and those obtained in the in vitro neutralization test in VERO cells (diphtheria antitoxin). It is concluded that the ToBI test is a simple and reliable alternative to the functional models currently in use for the estimation of diphtheria and tetanus antitoxin levels. In addition, the ToBI test eliminates the need for laboratory-animal or cell-culture facilities and can be performed with small quantities of serum as required in field trials.

Animals↗
PubMed1983

Studies on the molecular epidemiology of diphtheria.

DNA was extracted from toxigenic and nontoxigenic (tox+ and tox-) diphtheria bacilli isolated during a carrier survey that followed recovery of a tox+ Corynebacterium diphtheriae mitis from a baby with membranous tonsillitis. The electrophoretic gel patterns of restriction enzyme digests were indistinguishable from one another. They were, however, readily distinguishable from similar gels of DNAs extracted from diphtheria bacilli associated with outbreaks elsewhere. Hybridisation of a labelled nick-translated corynephage-beta c-DNA probe to nitrocellulose blots of these gels occurred only to blots from tox+ strains. Other hybridisation studies showed that all of seven strains, each isolated from a diphtheria case or carrier in a different part of the world, carried a prophage with DNA closely related to phage beta tox+. When an individual carrying a tox+ diphtheria bacillus arrives in an immunised community, spread of the tox gene to other individuals may be via phage conversion of tox- C diphtheriae already prevalent among the nasopharyngeal bacterial flora of the local populace, rather than by colonisation with the tox+ strain itself.

Autoradiography↗
PubMed2000

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: 184969 doses of D or DT vaccine were given to 99939 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.

Adult↗
PubMed2001

Booster response to the tetanus and diphtheria toxoid carriers of 11-valent pneumococcal conjugate vaccine in adults and toddlers.

We measured the tetanus and diphtheria antitoxin responses after administration of one dose of a mixed carrier (tetanus and diphtheria toxoids) 11-valent pneumococcal conjugate vaccine (PncDT) in 20 Finnish adults (mean age 26.1 years) and 20 Finnish (mean age 23.2 months) and 23 Israeli (mean age 18.5 months) toddlers. The vaccinees had previously been immunised with multiple doses of vaccines containing diphtheria and tetanus toxoids. A double-antigen ELISA was used to measure the antitoxin concentrations. PncDT induced significant booster responses in both adults and toddlers to the tetanus and the diphtheria carrier proteins. Thus, the effect on the tetanus and diphtheria immunity of multivalent conjugate vaccines containing tetanus and diphtheria toxoids as carriers needs to be evaluated before such vaccines are routinely implemented.

Adult↗
PubMedDate not supplied

Rational approaches to reduce adverse reactions in man to vaccines containing tetanus and diphtheria toxoids.

Adverse reactions to routine vaccines are obstacles to the mass vaccination campaigns. Though the absolute safety of any injectable vaccine cannot be guaranteed, the adverse side effects to vaccines can be minimized by practicing existing scientific knowledge. Adverse side effects to tetanus and diphtheria toxoids have been known for many years and there have been ways to minimize these reactions. These procedures did not get wide acceptance, because the current partially purified tetanus and diphtheria vaccines meet the regulatory requirements and the manufacturers are reluctant to change the established procedures of production due to the amount of work involved in the regulatory issues under the current Good Manufacturing Practices (GMP). Due to the recent epidemic of diphtheria in the independent states of the former Soviet Union, and its potential for spread to other European Countries, vaccination campaigns with tetanus and diphtheria vaccines received a new boost with several international agencies. In this report, we review the causes for adverse reactions to tetanus and diphtheria vaccines and offer practical suggestions for minimizing these reactions. The major issues in minimizing adverse reactions to these vaccines include: (1) purifying the toxins before detoxification as the reactogenic accessory antigens get covalently bound to the toxins during detoxification; (2) either using well-tolerated adjuvants which do not elicit the production of antigenic specific IgE antibodies responsible for adverse reactions or by using non-adjuvanted highly immunogenic polymerized antigens; (3) checking the status of immunity by recently developed rapid serological methods or by the Schick skin-test for diphtheria to avoid allergic or Arthus-type reactions. These approaches are applicable to industrial scales and would result in a pure, less reactogenic and better characterized toxoids antigens which would be more suitable for combined vaccines comprising highly purified acellular pertussis components, polysaccharide-protein conjugates and other antigens.

Adjuvants, Immunologic↗
PubMed1997

Analysis of heterogeneity of Corynebacterium diphtheriae toxin gene, tox, and its regulatory element, dtxR, by direct sequencing.

The largest diphtheria outbreak in the developed world since the 1960s is in progress in the Russian Federation. Seventy-two Corynebacterium diphtheriae strains from throughout Russia and the Ukraine, selected for temporal and geographic diversity, and 6 reference and control strains were assayed by DNA direct sequencing, and DNA sequences of their diphtheria toxin gene, tox, and the regulatory dtxR gene, were compared to those of the Park-Williams no. 8 strain (PW8). Twenty-eight C. diphtheriae strains had entire tox sequences identical to that of the PW8 strain. Among the remaining 40 strains which were toxigenic, 4 point mutations were detected in the tox gene, one within the A and three within the B subunit gene. All four were silent mutations, indicating that diphtheria toxin is highly conserved at the amino acid sequence level; therefore, changes in the efficacy of the current vaccines would be unlikely to occur. Within the open reading frame of the regulatory dtxR gene, 35 point mutations were detected. Only 15 strains had entire dtxR sequences identical to that of the PW8 strain. Nine amino acid substitutions were found in the carboxyl half of dtxR: 22 and 25 strains differed from the PW8 strain in one and two amino acids, respectively. Given that naturally occurring variations of dtxR might be associated with increased diphtheria toxin production, studies to investigate the association of these point mutations and amino acid substitutions with quantified toxin production in the strains causing the current epidemic are under way.

Amino Acid Sequence↗
PubMed1997

Immunity to diphtheria in Siena.

The aim of this study, carried out in 1993, was to evaluate diphtheria immunity in Siena. Diphtheria antitoxin levels were measured by means of the immunoenzymatic test (ELISA) in serum samples of 602 apparently healthy subjects (239 males and 363 females) of all ages residing in Siena. According to widely used criteria, 6% of the total population were susceptible to diphtheria (antibody levels < 0.01 IU/ml), 71% had basic protection (0.01-0.09 IU/ml) and 23% were fully protected (> or = 0.1 IU/ml). The results suggested that a high proportion of young population had a protective level of immunity against diphtheria, that susceptibility increased with age and a smaller proportion of males (2.9%) than females (8.3%) were unprotected; this difference was statistically significant. Our results suggest that it may be useful to revaccinate adults with low levels of diphtheria toxoid so that the percentage that remains unprotected does not put the community at risk of an outbreak of diphtheria.

Adolescent↗
PubMed2000

Evidence of increased carriage of Corynebacterium spp. in healthy individuals with low antibody titres against diphtheria toxoid.

This study evaluated whether a correlation exists between carriage of corynebacteria and the lack of immunity to diphtheria toxoid. Samples of both nasal and pharyngeal secretions were taken from 500 apparently healthy subjects of both sexes and of all ages and inoculated onto Tinsdale's medium. A serum sample was also taken for ELISA test to determine the titre of diphtheria toxin antibodies. None of the subjects carried Corynebacterium diphtheriae. Ninety-three strains of Corynebacterium spp. were isolated from 93 subjects and 86 of these were classified to species or group level by biochemical tests. C. xerosis was the most common (25.8%) followed by C. pseudodiphthericum (16.1%), C. jeikeium and C. striatum (both 10.8%), and C. urealyticum (9.7%). Three other species accounted for approximately 20% of strains and seven were unclassified as biochemically atypical corynebacteria. Non-protective antibodies to diphtheria toxin were found in 80 of the 93 subjects and a strong statistical association was demonstrated between carriage of corynebacteria and non-protective levels of anti-toxin antibodies. The remaining 13 subjects had protective levels of antitoxin antibodies. In contrast, only 45 of the 407 non-colonized subjects had non-protective antitoxin titres. The prevalence of carriage increased with age among males as did the percentage of non-protected subjects. The prevalence of female carriers of corynebacteria was significantly lower. Serum samples from 12 subjects with different antibody titres to diphtheria toxoid reacted to varying degrees with whole-cell lysates of a number of species of corynebacteria. The results suggest that a causal relationship may exist between nasopharyngeal carriage of corynebacteria and a low anti-diphtheria toxin immune response.

Adolescent↗