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Diphtheria: Epidemiological update and review of prevention and control strategies
Abstract
The importance of anti-diphtheria immunity in adults through periodic booster doses of vaccine is now increasing after last years diphtheria outbreaks in Newly Independent States (NIS) and Algeria and a few cases found in Europe and USA. Diphtheria cases notified in Italy between 1991-1994 have been reported. In 1995 WHO outlined the need to review vaccination schedules against diphtheria in all countries where gaps occur in the immunity of adults. The main sero-epidemiological studies performed in adults and vaccination schedules against diphtheria in some industrialized countries have been examined. Actual situation and control strategies adopted by WHO in the NIS and implications for other countries have been briefly presented. Finally, guidelines for management, investigation and control of diphtheria have been reported, including CDCs recommendations.
It was reported that a mature woman, Mrs. S, 42 years old with several complaints and symptoms such as fever, swallowing pain
weak body, swollen tonsil with beslag, dirty uvula of mouth cavity and tongue, and bullneck. The final diagnosis indicated that the
patient was suspected diphtheria, candidiasis oris, sepsis, and pneumonia. The sudden death of the patient was probably caused bymyocarditis.
Background: Diphtheria, a leading cause of childhood mortality in the pre-vaccination era, has witnessed a resurgence in the last decade in the developing world and in parts of Europe. Faucial diphtheria can mimic acute tonsillitis and glandular fever, and a degree of clinical suspicion is required in order to diagnose and treat a potentially life-threatening condition. This assumes greater significance in today's world. Objective: To review the number of diphtheria cases admitted to Silchar Medical College and Hospital, a teaching hospital in the state of Assam in India over the last 5 years and to compare the profile of patients admitted here to cases reported elsewhere in the country and abroad. Methods: Details of patients were obtained from the hospital database. Comparisons were made with disease patterns reported elsewhere in the country and in parts of Europe in the late 1980s and 1990s. Results: A total of 101 patients were admitted with diphtheria over a period of 5 years (March 1997–March 2002). There were no peaks in the incident rate. About 82% of the patients admitted were below the age of 15. One adult with microbiologically confirmed diphtheria was seen. Immunisation status varied between no cover (70%), incomplete immunisation (20%), and full immunisation (10%). A majority of patients were from the rural environment and were economically disadvantaged. Treatment involved the administration of anti-diphtheritic serum (diphtheria antitoxin), IV Penicillin, and where indicated, tracheostomy. Conclusions: Results obtained show an endemic pattern of the disease in this part of the world. Persistence of the disease is due to poor immunisation coverage and problems such as poor hygiene associated with poverty. There is a rural preponderance of cases as opposed to the epidemics reported elsewhere in the country, the newly independent states of the former Soviet Union, and in parts of the USA. The case of the adult points to an interesting change in the normal age distribution of the disease.
Die Gattung Corynebacterium gehört, neben Mycobacterium, Nocardia, Rhodococcus und weiteren nahverwandten Gattungen, dem unverwechselbaren, gattungsübergreifenden Taxon Mycolata an. Viele Spezies aus dieser heterogenen Gruppe Mycolsäure-haltiger Actinomyceten sind entweder aufgrund ihrer medizinischen oder ihrer biotechnologischen Bedeutung bekannt. Beispielsweise zählen Mycobacterium tuberculosis, Mycobacterium leprae, Corynebacterium diphtheriae und Nocardia farcinica, welche weltweit Verursacher besonders gefährlicher bakterieller Infektionskrankheiten sind, zu dieser ungewöhnlichen Gruppe Gram-positiver Bakterien. Ebenso bedeutsam sind einige apathogene Mycolata-Arten, die industrielle Anwendung finden. Corynebacterium glutamicum und Corynebacterium efficiens sind leistungsfähige Bakterien, die zum Beispiel in der Produktion des Geschmacksverstärkers Glutamat und des Tierfuttermittelzusatzes Lysin eingesetzt werden, während verschiedene Rhodococcus Spezies Anwendung bei der Herstellung von Acrylsäuren finden. Die Zellwand der Mycolata zeigt, verglichen mit der klassischer Gram-positiver Bakterien, eine außergewöhnliche Zusammensetzung und Struktur auf. Abgesehen von einem Arabinogalactan-Peptidoglycan-Komplex enthält die Zellwand der meisten Actinomyceten einen hohen Anteil an Mycolsäuren. Diese langkettigen, verzweigten Fettsäuren formen eine, mit der äußeren Membran Gram-negativer Bakterien vergleichbare, stark undurchlässige, hydrophobe äußere Hülle, welche die Grundlage der außergewöhnlichen Medikamentenresistenz bei den Mycolata bildet. Wie die äußere Membran Gram-negativer Bakterien enthält die Zellwand der Mycolata porenformende Proteine, die den Durchlass hydrophiler Substanzen gestatten. Indem sie eine Verbindung zwischen dem Zellinneren und der Umwelt, in der das Bakterium lebt, schaffen und einen kontrollierten Austausch zwischen beiden ermöglichen, tragen die Kanalproteine entscheidend zur Funktion der bakteriellen Zellhülle bei. Das Ziel dieser Arbeit war das Wissen über Zellwandkanäle in Corynebakterien zu erweitern. Deshalb untersuchten wir PorA und PorH Proteine, die basierend auf früheren Studien Zellwandkanälen in C. glutamicum, C. efficiens und Corynebacterium callunae zugeordnet werden, um ungeklärten Fragen nachzugehen und um Wissen über deren Struktur zu erlangen. Ferner inspizierten wir Zellwände pathogener Corynebakterien, genauer gesagt von Corynebacterium diphtheriae und Corynebacterium jeikeium, um herauszufinden, ob diese Spezies wie ihre harmlosen Verwandten Kanalproteine besitzen. In dieser Arbeit wiesen wir mit C. diphtheriae und C. jeikeium in zwei weiteren Corynebacterium-Arten offene, mit Wasser gefüllte Zellwandkanäle nach. Des Weiteren stellten wir fest, dass sich die Zellwandkanäle von C. glutamicum, C. efficiens und C. diphtheriae aus zwei Proteinen zusammensetzen, einem zugehörig zu der Gruppe der PorH Proteine und einem weiteren aus der Gruppe der PorA Proteine. Diese heteromere Struktur von Zellwandkanälen bei Corynebakterien stellt ein Novum für Zellwandkanäle bei den Mycolata dar. Indessen besteht der Zellwandkanal von C. jeikeium aus nur einem Protein, CjPorA, angeordnet zu einem Oligomer. Obgleich das Molekulargewicht dieses Proteins (4 kDa) mit dem von PorH und PorA Proteinen vergleichbar ist (5-7 kDa), weißt seine Primärsequenz keine eindeutige Homologie zu diesen auf. Dennoch deutet vieles auf eine Verwandtschaft zwischen CjPorA und PorH/PorA Proteinen hin, da das Gen jk0268, welches für CjPorA kodiert, sich in einer Region des C. jeikeium Chromosoms befindet, die der Genomregion entspricht in welcher die porH/porA Gene der anderen Corynebakterien lokalisiert sind. Dies lässt vermuten, dass jk0268 (welches für den homomeren Zellwandkanal in C. jeikeium kodiert) und die porH/porA Gene von C. glutamicum, C. efficiens und C. diphtheriae (die einen heteromeren Zellwandkanal kodieren) wahrscheinlich Nachkommen eines gemeinsamen Vorläufergens sind. Phylogenetische Analysen der Gattung Corynebacterium unterstützen diese Annahme. Desweitern legen sie nahe, dass die hier untersuchten Zellwandkanäle innerhalb dieser Gattung wahrscheinlich weit verbreitet sind. Ein umfassendes Wissen über Zellwandkanäle, denen beim Transport gelöster Stoffe über die äußere Membran in Corynebakterien und anderen Mitgliedern der Mycolata eine entscheidende Rolle zukommt, könnte von großem wirtschaftlichem und medizinischem Nutzen sein. The genus Corynebacterium belongs, together with Mycobacterium, Nocardia, Rhodococcus and further closely related genera, to the distinctive suprageneric taxon mycolata. Many species within this diverse group of mycolic acid containing actinomycetes are known either because of their medical or biotechnological relevance. For instance, Mycobacterium tuberculosis, Mycobacterium leprae, Corynebacterium diphtheriae and Nocardia farcinica, causer of most dangerous bacterial infectious diseases world-wide, are among this exceptional group of Gram-positive bacteria. Likewise of importance are some harmless mycolata species which find use in industrial settings. Corynebacterium glutamicum and Corynebacterium efficiens are, e.g., potent producers of the flavour enhancer glutamate and the animal feed additive lysine, while several Rhodococcus species are applied in the production of acrylic acids. The cell wall of mycolata species, compared with that of Gram-positive bacteria, exhibits an unusual composition and organization. Besides an arabinogalactan-peptidoglycan complex, the cell walls of most actinomycetes contain large amounts of mycolic acids. Comparable to the outer membrane of Gram-negative bacteria, these long-chained branched fatty acids form a highly impermeable hydrophobic outer layer which provides the basis of the exceptional drug resistance of mycolata species. Like the outer membrane of Gram-negative bacteria, the cell wall of mycolata contains channel-forming proteins that allow the passage of hydrophilic solutes. By permitting and controlling the exchange and communication between the interior of the cell and the environment in which the bacterium lives, the channels play an important role for the function of the bacterial cell envelope. This thesis aimed to extend our knowledge about cell wall channels in corynebacteria. For this purpose, we examined PorA and PorH proteins that have been associated by previous studies with cell wall pores in C. glutamicum, C. efficiens and Corynebacterium callunae in order to resolve unanswered questions and to gain structural knowledge. We also investigated cell walls of pathogenic corynebacteria, in particular of Corynebacterium diphtheriae and Corynebacterium jeikeium, to investigate if these species possessed channels as is the case with their harmless relatives. In this work we provided evidence for the existence of large and water-filled cell wall channels in C. diphtheriae and C. jeikeium. Moreover, we demonstrated that the major cell wall channels of C. glutamicum, C. efficiens and C. diphtheriae consist of two distinctive polypeptides; one of whom belongs to the class of PorH proteins and the other to the class of PorA proteins. This heteromeric structure of channels of corynebacteria represents a novelty for channels of the mycolata. In contrast, the C. jeikeium channel is solely constituted by a single protein, CjPorA, arranged as an oligomer. Although the molecular mass of this protein (4kDa) is comparable to those of PorH and PorA proteins (5-7 kDa), it shares no distinctive homology in its primary sequence with them. However, there is evidence for relationship between CjPorA and PorH/PorA proteins because the gene jk0268, coding for CjPorA, is localized in a chromosomal region of C. jeikeium that corresponds to the genomic region containing the porH/porA genes in the other corynebacteria. This suggests that jk0268 (coding for the homomeric cell wall channel in C. jeikeium) and the porH/porA genes of C. glutamicum, C. efficiens and C. diphtheriae (coding for heteromeric cell wall channels) are presumably descendants of a common ancestor gene. This assumption gets support from data on phylogenetic analysis of the genus Corynebacterium. Moreover, these data suggest that the here investigated cell wall channels are presumably widespread within this genus. A profound knowledge of cell wall channels, building the main passage of solutes through the outer mycolate membrane in corynebacteria and other members of the mycolata, can be of great economical and medical value.
The national immunisation programme in the Netherlands is very effective and safe. To improve the success and effectiveness of the immunisation programme, vaccination of other (age)groups is indicated. Extension of the programme with new target diseases can result in considerable health gain for some diseases. The target diseases are largely under control. However, monitoring the effectiveness of the programme is important. Maintaining high vaccin uptake is vital to prevent (re)emergence of disease. Vaccination of (young) adults now (pertussis) and in the future (mumps, measles, rubella, hepatitis B) could give further improvement. Also other vaccination strategies need attention such as maternal or newborn vaccination for pertussis. The switch to a DTPa-IPV/Hib combination vaccine in 2005 should be monitored carefully both for pertussis and other components. The national immunisation programme could be extended with new target diseases. Pneumococcal vaccination for children is expected to give important health gain. The desirability to introduce varicella vaccination - possibly in combination with mumps, measles and rubella - needs further study. When effective and safe vaccines become available for meningococcal serogroup B, respiratory syncytial virus and human papillomavirus, extension of the immunisation programme might be advisable. Extension of the programme with available vaccines for influenza, hepatitis A or tuberculosis is not (yet) recommended. For these diseases the current policy needs to be continued, possibly with lowering the age of influenza vaccination from 65 years to 50 years of age. The desirability to vaccinate children against influenza needs additional investigation, like pneumococcal vaccination for elderly. Vaccination against HSV-2 or rotavirus is not possible yet. The health gain is expected to be limited for HSV-2. When a vaccine for rotavirus comes available a cost-effectiveness analysis is needed. Het Rijksvaccinatieprogramma in Nederland is zeer effectief en veilig. Om het succes en de effectiviteit van het vaccinatieprogramma te vergroten, is vaccinatie van andere (leeftijds)groepen aan te bevelen. Uitbreiding van het programma met nieuwe doelziekten kan voor een aantal ziekten aanzienlijke gezondheidswinst opleveren. De ziekten waartegen wordt gevaccineerd zijn grotendeels onder controle, maar bewaking van de effectiviteit van het programma is van groot belang. Handhaven van de hoge vaccinatiegraad is essentieel om terugkeer van de ziekten te voorkomen. Vaccinatie van (jong) volwassenen nu (kinkhoest) of in de toekomst (bof, mazelen, rodehond, hepatitis B) zal verder verbetering kunnen geven. Ook andere vaccinatiestrategieen verdienen aandacht, zoals vaccinatie van pasgeborenen of aanstaande ouders. De vervanging van het huidige difterie, tetanus, poliomyelitis, hele-cel kinkhoest en Haemophilus influenzae vaccin (DKTP/Hib) door een combinatievaccin met een a-cellulaire kinkhoestcomponent (DKATP/Hib) ingevoerd begin 2005 moet nauwkeurig worden gemonitored, zowel voor kinkhoest als de overige vaccincomponenten. Het Rijksvaccinatieprogramma kan met vaccins tegen andere ziekten uitgebreid worden. Pneumokokken-vaccinatie van kinderen levert belangrijke gezondheidswinst op. De wenselijkheid om waterpokken-vaccinatie te introduceren - mogelijk in een combinatievaccin met bof, mazelen en rodehond - moet bestudeerd worden. Als tegen meningokokken B, respiratoir syncytieel virus en humaan papillomavirus effectieve en veilige vaccins op de markt komen, is uitbreiding van het vaccinatieprogramma naar verwachting raadzaam. Dit geldt (nog) niet (of in mindere mate) voor de al beschikbare vaccins tegen influenza, hepatitis A en tuberculose. Voor deze ziekten is continuering van het huidige beleid nodig met mogelijke verlaging van de leeftijd voor influenzavaccinatie van 65 jaar naar 50 jaar. De wenselijkheid van vaccinatie van kinderen tegen influenza is een punt voor nader onderzoek, evenals pneumokokken-vaccinatie van ouderen. Vaccinatie tegen herpes simplex virus-2 en rotavirus is nog niet mogelijk. Vaccinatie levert naar verwachting relatief beperkte gezondheidswinst op voor herpes simplex virus-2. Als een rotavirus vaccin beschikbaar komt is een kosten-effectiviteitsanalyse aangewezen.
Mass vaccination can change the epidemiological dynamics of infectious diseases. It may result in a limited persistence of natural and vaccine-induced immunity and a higher mean age of infection, which may lead to a greater risk of complications. The epidemiological situation should be monitored and immunosurveillance based on the assessment of specific antibodies against vaccine-preventable diseases in human serum is one of the tools. In order to estimate the immunity of the Dutch population reliably, a large-scale, population-based, collection of serum samples was established (8359 sera in a nation-wide sampling and 1589 sera from municipalities with low vaccine coverage). In contrast to collecting residual sera from laboratories, this approach gains extensive information by means of a questionnaire regarding the determinants of the immune status and the risk factors for the transmission of infectious diseases in general. The population-based approach gives a better guarantee that the data are representative than collecting sera from laboratories does.
In a population-based study in the Netherlands, diphtheria antitoxin antibodies were measured with a toxin-binding inhibition assay in 9, 134 sera from the general population and religious communities refusing vaccination. The Dutch immunization program appears to induce long-term protection against diphtheria. However, a substantial number of adults born before the program was introduced had no protective diphtheria antibody levels. Although herd immunity seems adequate, long-term population protection cannot be assured. As more than 60% of orthodox reformed persons have antibody levels lower than 0.01 IU/ml, introduction of diphtheria into religious communities refusing vaccination may constitute a danger of spread of the bacterium.
We present the case of a 37-year-old Afghani man with a history of childhood diphtheria, who was diagnosed with bilateral vocal cord paralysis at age 15 years. At about this time he developed progressive muscular wasting and distally predominant weakness, and subsequently developed respiratory insufficiency, necessitating nocturnal ventilatory support. His examination suggested a distal symmetric sensorimotor neuropathy, and his brother was similarly affected, although to a lesser degree. Electromyography (EMG) and nerve conduction studies revealed this process to be purely axonal. A diagnosis of possible hereditary motor and sensory neuropathy (HMSN) type IIc, hereditary axonal polyneuropathy with vocal cord paralysis, is proposed, although the question of early diphtheritic involvement of the vocal cords and peripheral nerves is also considered.
The diphtheria epidemic in eastern Europe and the worldwide increase in diphtheria morbidity have sparked discussion on whether people in western Europe are adequately protected.1 2 In western Europe, the effectiveness of long term protection afforded by immunisation programmes is under debate.
In Belgium, the national immunisation programme against diphtheria was introduced in 1959. Vaccination was recommended for all infants, and a catch up programme for children up to the age of 15 years was also instituted. The programme comprises four doses of toxoid, given at age 3, 4, 5, and 15 months. The vaccine is a combination of diphtheria, pertussis, and tetanus toxins, and 95% of children are covered.3 We evaluated the effectiveness of the current recommended adult booster immunisation of a single, low dose diphtheria vaccine.
Altogether 176 …
Laboratory confirmation of pertussis by culture, PCR, or detection of antibody increase in paired sera is hampered by low sensitivity in the later stages of the disease. Therefore, we investigated whether, and at which level, concentrations of immunoglobulin G (IgG) antibodies against pertussis toxin (PT), IgG-PT, in a single serum sample are indicative of active or recent pertussis. IgG-PT, measured by enzyme-linked immunosorbent assay in units per milliliter, was analyzed in 7,756 sera collected in a population-based study in The Netherlands, in the sera of 3,491 patients with at least a fourfold increase of IgG-PT, in paired sera of 89 patients with positive cultures and/or PCR results, and in the sera of 57 patients with clinically documented pertussis with a median follow-up of 1.4 years. We conclude that, independently of age, IgG-PT levels of at least 100 U/ml are diagnostic of recent or active infection with Bordetella pertussis. Such levels are present in less than 1% of the population and are reached in most pertussis patients within 4 weeks after disease onset and persist only temporarily.
Kinghorn GR, Duerden BI, Hafiz S 1986 British Journal of Obstetrics and Gynaecology 93: 869. Lambe DW, Danielsson D et al. 1 975 Journal of Infectious Diseases 131: 499. Langworth BF 1977 Bacteriological Reviews 41: 373.
The reaction rates and immunogenicity of primary immunization with tetanus (5 flocculation [Lf] units) and diphtheria (1.5 Lf units) toxoids were evaluated in older children and adults. Eight of 42 subjects had local reactions to one or more doses of vaccine. All subjects had protective titers to tetanus and 94% to diphtheria after two injections. Titers of antitoxins were greater in younger patients; in those younger than 19 years, they were inversely related to age.
(JAMA 1982;248:2478-2480)
Tetanus and diphtheria antitoxin levels were measured in 183 urban adults, using a hemagglutination technique. Protective levels (greater than 0.01 unit/mL) of tetanus antitoxin were present in more than 85% of sera from all subjects under 40 years of age and from men between 40 and 59 years old. A minority of women (36%) between 40 and 59 years of age, and of men (41%) and women (29%) over 60 years of age, were protected. Less than one quarter of the study group had protective levels (greater than 0.01 unit/mL) of diphtheria antitoxin. The results of the study suggest that a minority of middle-aged women and older adults have been appropriately immunized against diphtheria and tetanus.
The diphtheria immunity status was determined with the passive haemagglutination technique in 503 sera of 10-90-year-old persons from Warsaw and Olsztyn Provinces. Donors of sera were students, teachers, pregnant women, employees of industry and medical service. The immunity was highest (90% of titers 0.1 IU/ml or higher) in persons below 20 years of age and in persons above 60 years of age (55%). Between these two groups, gaps in immunity exist, the proportion of those immune varying from 36-50% in the 20- 60-year-old groups. Since a large pool of susceptible persons creates an epidemic potential it was suggested that the adult type of tetanus-diphtheria toxoid (Td) should be introduced into the routine immunization schedule for high risk groups. These groups might include professional or age groups who are vulnerable to reintroduction of virulent Corynebacterium diphtheriae such as kindergarten and creches personnel, teachers, students, military service personnel and persons travelling to developing countries.
A sample of 643 healthy subjects from central Italy aged 20 to 80, were screened for diphtheria antitoxin. Serum diphtheria antitoxin was assayed by a new passive haemagglutination technique using turkey red blood cells sensitized with diphtheria toxoid, after having performed a correlation study between this technique and the reference in vivo neutralization test. Of the studied population 26.7% showed a lack of serum antitoxin titres considered to be protective. The rate of susceptible subjects increased with age, showing the highest value (38.9%) in the sixth decade of age. Males proved less protected than females; 53.2% of the male population aged 50-59 were lacking a protective anti-diphtheria immunity. On the basis of present results, a periodical revaccination of the entire adult population with reduced doses of diphtheria toxoid would be advisable.
Despite mass vaccination against diphtheria, many people have antibody titers below the protective level of 0.01 IU per milliliter. A recent outbreak of diphtheria in Sweden caused 17 clinical cases of diphtheria in the city of Göteborg; three of the patients died. A satellite outbreak occurred in Stockholm after a few months' delay. Using a new genetic probe, we analyzed 36 strains of Corynebacterium diphtheriae isolated in Sweden and Denmark during the period 1976 to 1986. Although the 36 strains can be classified in 17 different groups of C. diphtheriae (several of them containing toxigenic strains), all the clinical and fatal cases of diphtheria were caused by isolates from the same group, strongly suggesting that the outbreak in Sweden was caused by a single strain that possibly had a virulence factor separate from toxigenicity. This strain may have been imported into Sweden from Denmark, since it was isolated for the first time in Copenhagen in 1983, before the outbreak in Sweden.
Recommendations to give adults diphtheria and tetanus toxoid every ten years have been based on serological surveys that have shown lower antibody levels in older populations. The purpose of an immunisation programme, however, is to prevent disease and not merely to produce antibodies. In Canada, although an immunisation programme against diphtheria has been in operation for nearly sixty years, age-specific morbidity and mortality rates for diphtheria do not show an increase with age. Similarly, age-specific death rates from tetanus do not show any increase. From Canadian surveillance data, there is no evidence to suggest that people are leaving the immune pool and entering the susceptible pool. Immunisation programmes do not need to include routine administration of booster doses of diphtheria and tetanus toxoids to adults since the benefits of the procedure do not justify the risks or costs. Continuing case-surveillance will bring to light any increase in incidence of disease justifying a need for an adult programme.
A low dose (1.5 Lf) diphtheria vaccine for use in adults was given to 310 university student volunteers whose diphtheria antitoxin titres were less than 0.1 IU per ml. The incidence of adverse reactions was low. Postimmunisation blood samples taken from 134 of the students showed that in susceptible vaccinees the vaccine induced titres of antitoxin were consistent with protection and that it boosted the titres of those whose immunity was low.