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Respiratory diphtheria is an acute communicable upper respi-ratory illness caused by toxigenic strains of Corynebacterium diphtheriae, a Gram-positive bacillus. The illness is character-ized by a membranous inflammation of the upper respiratory tract, usually of the pharynx but sometimes of the posterior nasal passages, larynx, and trachea, and by widespread damage to other organs, primarily the myocardium and peripheral nerves. Extensive membrane production and organ damage are caused by local and systemic actions of a potent exotoxin produced by toxigenic strains of C. diphtheriae. A cutaneous form of diphtheria commonly occurs in warmer climates or tropical countries.

HISTORY OF THE DISEASEHistorical descriptions of diphtheria-like illness (throat mem-brane, neck swelling, frequent suffocation) first appeared in ancient Egyptian writings from the second millennium BC1 with increasingly detailed descriptions by Greek writers, including Hippocrates (fifth century BC), Aretaeus (second century AD), and Aëtius (sixth century AD).2–4 Only isolated reports of the disease appeared until the 17th century, when devastating outbreaks occurred in Spain.3 Indeed, in Spanish history, 1613 is known as the Year of Diphtheria (Año de los Garrotillos).2 Successive outbreaks occurred in southwestern Europe approximately every 12 years through the 18th century. The earliest definitive description of diphtheria in America was that of Samuel Bard in New York in 1771, although outbreaks had previously been noted in the American colonies.2,3,5 In the early 19th century, Bretonneau clearly delineated the clinical picture of diphtheria, convincingly argued for its communica-bility, successfully pioneered tracheostomy as a method of treatment, and gave the disease its name, derived from the Greek word for leather or tanned skin.2,3

In the second half of the 19th century, increasingly severe epidemics swept many parts of Europe and the large cities of the United States, and vigorous efforts were made by research-ers in the new field of bacteriology to identify the causative agent.4 In 1883, Klebs first described the characteristic organ-isms in stained preparations of diphtheritic membranes, and Löffler reported the successful growth of these organisms in culture a year later.3 Other investigators soon confirmed the pathogenicity of the organism for guinea pigs, and in 1888, Roux and Yersin demonstrated the presence of a potent exo-toxin (see “Passive Immunization,” later). Over the next decade, antisera produced in animals by injection of sublethal or inactivated cultures were first shown to prevent death in nonimmune animals that were challenged with virulent organisms, and then to prevent death in children with clinical diphtheria.2,3

The concept of active immunization began with Theobald Smith in 1907, who noted that long-lasting immunity to diph-theria could be produced in guinea pigs by the injection of mixtures of diphtheria toxin and antitoxin and suggested that these mixtures might do the same for humans. After successful immunization of children by von Behring with toxin–antitoxin mixtures, immunization programs began in selected European and American cities. However, these immunizations, although usually effective, were not free of adverse reactions. In 1913,

19 Schick introduced a skin test for immunity that consisted of the injection of a small, measured amount of diphtheria toxin; in immune persons, circulating antibody neutralized the toxin, and no local lesion was observed.2 The Schick skin test was widely used to distinguish immune individuals and target immunization to those susceptible. In the early 1920s, Ramon showed that diphtheria toxin, when treated with heat and for-malin, lost its toxic properties but retained its ability to produce serologic protection against the disease. Thus the current immunizing preparation, diphtheria toxoid, came into being.6

WHY THE DISEASE IS IMPORTANTBefore the introduction of diphtheria immunization, diphthe-ria was a major cause of childhood mortality, and it remains endemic in many developing countries. A large outbreak of diphtheria in the newly independent states of the former Soviet Union in the 1990s highlighted the potential for this ancient scourge to reemerge in countries that fail to maintain high levels of population immunity through immunization.7

BACKGROUNDClinical DescriptionClassic diphtheria has an insidious onset after an incubation period of 1 to 5 days (rarely longer). The gradual onset of diphtheria is in contrast to the usually sudden, almost explo-sive manifestations of streptococcal pharyngitis. Symptoms of diphtheria are initially nonspecific and mild; throughout the course of the disease, the patient’s temperature usually does not exceed 38.5°C. Other early symptoms in children include diminished activity and some irritability. At the very onset of symptoms, the pharynx is inspected on examination but no membrane is present. About a day after onset, small patches of exudate appear in the pharynx. Within 2 or 3 days, the patches of exudate spread and become confluent and may form a membrane that covers the entire pharynx, including the tonsillar areas, soft palate, and uvula. This membrane becomes grayish, thick, and firmly adherent to the underlying mucosa. Efforts to dislodge the membrane result in bleeding. Anterior cervical lymph nodes become markedly enlarged and tender. In a proportion of patients, the lymph node swelling is associated with considerable inflammation and edema of the surrounding soft tissues, giving rise to the so-called bull-neck appearance, which is associated with a higher morbidity and mortality. Although fever is rarely high, the patient char-acteristically appears toxic and displays a rapid, thready pulse. In untreated patients, the membrane begins to soften about a week after onset and gradually sloughs off, usually in pieces but sometimes as a single unit. As the membrane detaches, acute systemic symptoms, such as fever, begin to disappear.

Although pharyngeal diphtheria is by far the most common form of disease seen in unimmunized populations, other skin or mucosal sites may be involved. Laryngeal diphtheria occurs in 25% of cases; in 75% of these instances, the pharynx is also involved. Isolated nasal diphtheria is uncommon (approxi-mately 2% of cases). Cutaneous, aural, vaginal, and conjunc-tival diphtheria together account for only approximately 2%

Diphtheria ToxoidTejpratap S.P. Tiwari and Melinda Wharton

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262 SECTION2 Licensed Vaccines and Vaccines in Development

local symptoms of diphtheria in the respiratory tract are resolv-ing and the patient is otherwise improving.

In either early or late myocarditis, a wide variety of clinical and electrocardiographic findings may be noted.24 Tachycar-dia, distant heart sounds, and a weak pulse may be observed. Electrocardiography most often shows conduction changes and alterations in T waves. Supraventricular and ventricular ectopic rhythms are common in severe diphtheria, even in the absence of evidence of heart failure.26 The earlier electrocar-diographic changes appear, the worse is the prognosis. Com-plete heart block frequently occurs and is usually fatal; ventricular pacing may not improve survival.27–30 Echocardio-grams show decreased contractility and ventricular dilation proportional to the severity of the clinical carditis; a left ven-tricular ejection fraction of less than 35% is associated with an increased risk for death.31,32 Although electrocardiograms and echocardiograms return to normal in most survivors, residual changes are seen in some survivors of severe carditis for up to several years after illness.26,31,33 Left bundle-branch block at hospital discharge has a poor prognosis.34

Neurologic complications of diphtheria are primarily toxic peripheral neuropathies, and they occur in approximately 15% to 20% of cases.35,36 The manifestations are more motor than sensory and usually begin 2 to 8 weeks after onset of the illness. In severe cases, palatal paralysis with consequent nasal voice and nasal regurgitation of ingested fluids may occur during the acute membranous phase, particularly with exten-sive pharyngeal disease, and are believed to be attributable to local effects of the toxin. With milder disease, palatal paralysis is common as late as the third week. Symmetric peripheral neuritis of the lower extremities is a frequent neurologic com-plication, usually occurring 3 to 10 weeks after onset of the infection. Diaphragmatic paralysis occasionally occurs, usually a month or more after onset, and may require mechanical respiratory support. Ocular paralysis, involving either the extraocular muscles or those of accommodation, sometimes appears, usually 5 or 6 weeks after onset. Fortunately, func-tional recovery from these neuropathies is the rule, even in severe disease.37 An association between diphtheria and delayed-onset hearing loss has also been reported.38

BACTERIOLOGYCorynebacterium diphtheriae is a slender, Gram-positive bacil-lus, usually with one end being wider, thus giving the often-described club-shaped appearance. On culture, particularly under suboptimal conditions, characteristic bands or granules appear. On smear, the organisms often have a “pick-up sticks” relationship, assuming parallel (palisade-like), or V- or L-type patterns. The organisms are resistant to environmental changes, such as freezing and drying. There are four biotypes of C. diphtheriae (gravis, mitis, belfanti, and intermedius), which historically were identified by colonial morphology and biochemical differences; however, in practice, only the inter-medius biotype can be distinguished reliably by colonial mor-phology.39 No consistent differences are found in severity of disease caused by different biotypes. Biotype differentiation is not supported by phylogenetic analyses.40

PATHOGENESIS AS IT RELATES TO PREVENTIONThe exotoxin produced by C. diphtheriae is by far the most important pathogenic factor associated with the organism. The extensive study of the biology of diphtheria toxin has pioneered many biomedical developments over the past century. The basic biology of diphtheria toxin, including its production and actions, has become reasonably well under-stood, although some gaps remain.41,42

of cases and are often secondary to nasopharyngeal infection. Laryngeal diphtheria may occur at any age, but is particularly likely to occur in children younger than 4 years. It is marked by an insidious onset with gradually increasing hoarseness and stridor. Fever is usually slight. The diagnosis is often missed or delayed when the pharynx is not simultaneously involved. Laryngeal diphtheria is associated with greater morbidity and mortality as a result of airway obstruction and the greater degree of toxin absorption from the extensive membrane.

Cutaneous diphtheria is an indolent skin infection that often occurs at sites of burns or other wounds and may act as a source of respiratory infection in others.8–12 It is more common in warmer climates and in poor social conditions.8–11 Although sufficient diphtheria toxin is absorbed from skin lesions to frequently produce immunity, systemic complications are uncommon with cutaneous diphtheria. In warmer climates, the high incidence of cutaneous diphtheria appears to have played a major role in producing immunity in the population in the absence of high rates of respiratory diphtheria.

Invasive disease caused by C. diphtheriae occurs rarely, most commonly as a result of nontoxigenic strains. Bacteremia, endocarditis, osteomyelitis, and arthritis have been reported.13–17 Molecular epidemiology studies show that several of the reported clusters of invasive disease were associated with clon-ally related organisms.18–20

ComplicationsThe impact of diphtheria is largely measured by complica-tions attributable to the local disease and to the effect of absorbed toxin on other organs. The major threat from laryn-geal diphtheria is respiratory obstruction. Life-endangering obstruction is generally managed by tracheostomy. Even with a tracheostomy tube in place, fatal acute respiratory obstruc-tion occasionally occurs when a portion of a laryngeal mem-brane is dislodged and aspirated. The membrane may extend down into the tracheobronchial tree, resulting in pneumonia and expiratory respiratory obstruction. Because of edema of the upper respiratory tract, pharyngeal and nasal diphtheria are frequently associated with secondary otitis media and sinusitis.

The majority of deaths from diphtheria result from the effects of absorbed diphtheria toxin on various organs; severe complications from toxin absorption include acute systemic toxicity, myocarditis, and neurologic complications, primarily peripheral neuritis. The risk for complications is directly pro-portional to the extent of local disease, presumably because of increased production and absorption of the toxin in larger membranes. In addition, the frequency of these various com-plications appears to vary considerably between epidemics, for which no clear explanation is available. In the past, it was erroneously believed that the severity of the disease could be related to strains of the organism that were morphologically different on culture, being designated gravis, intermedius, and mitis.21,22 A possible explanation for variation in reported fre-quency of complications is variability in the timeliness of therapy with diphtheria antitoxin, as well as differences in susceptibility among affected populations.

Severe acute systemic toxicity with myocardial involvement usually occurs between the third and seventh day of the illness; many investigators classify this complication as early myocar-ditis.23 Others, however, believe that the effects on the myocar-dium are only part of diffuse systemic toxicity, including fever, purpura, peripheral circulatory collapse, restlessness, somno-lence, and disturbances of carbohydrate metabolism.24,25 This so-called early myocarditis is usually fatal. Late myocarditis usually appears in the second or third week of illness, when the


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19type-specific immunity. Lack of immunity to K antigens appears to be responsible for the fact that local upper respira-tory tract diphtheria can occur with non–toxin-producing organisms, and toxin-producing organisms may infect persons with ample serum antitoxin levels, but neither of these instances is associated with systemic manifestations, even though a faucial membrane is produced.55 Another factor responsible for the local invasiveness of the organism is the so-called cord factor, which is a toxic glycolipid. This glyco-lipid has been shown to disrupt mitochondria, depress cell respiration, and interfere with oxidative phosphorylation.56 The term cord factor is derived from a similar substance found in Mycobacterium tuberculosis that results in the growth of the organism in serpentine coils. Undoubtedly, there are other factors as well that help C. diphtheriae establish residence and provide nutritional substrates.

Some strains of two other closely related Corynebacterium species, Corynebacterium ulcerans and Corynebacterium pseudo-tuberculosis, have been demonstrated to produce diphtheria toxin,57 and nontoxigenic strains can be converted to toxi-genic strains by infection with β-corynebacteriophage.58 Sequencing studies demonstrate that both the base-pair sequence of the tox genes and the amino acid sequence of the diphtheria toxins from C. diphtheriae and C. ulcerans differ by approximately 5%.59 Disease indistinguishable from that caused by toxigenic strains of C. diphtheriae is associated with C. ulcerans infection.60–63

DIAGNOSISDiphtheria is rare in the United States. However, physicians need to be aware of the signs and symptoms that suggest diphtheria. Some developing countries continue to have high levels of circulation of toxigenic strains of C. diphtheriae. Some circulation persists in a few countries of the former Soviet Union after a large epidemic in the 1990s,64,65 and until recently limited persisting foci were reported in some highly developed countries.66,67

In countries where the disease is endemic, a patient with confluent pharyngeal exudate should be suspected of having diphtheria until proven otherwise. The onset is usually gradual over the course of 1 to 2 days and is associated with low-grade fever. The hallmark of respiratory diphtheria is the presence of pseudomembrane in the pharynx. Although certain clinical characteristics of membranous pharyngitis caused by diphthe-ria, such as the color, adherence, and odor of the membrane, can be recognized as being different from other forms of exu-dative pharyngitis by experienced clinicians, very few physi-cians in industrialized countries currently have the experience required to base a differential diagnosis on the clinical appear-ance of the lesion.

Because laryngeal diphtheria usually occurs concomitantly with pharyngeal involvement, membranous pharyngitis with stridor should be considered to be diphtheria until proved otherwise. However, about a quarter of all cases of laryngeal diphtheria do not display a pharyngeal lesion and therefore may often be misdiagnosed. The differential diagnosis includes epiglottitis caused by Haemophilus influenzae type b (Hib), although uncommon in immunized populations, spasmodic croup, the presence of a foreign body, or viral laryngotracheo-bronchitis. There should be little confusion regarding the first three because the onset and clinical characteristics of each are well known and are different from diphtheritic croup, which is ordinarily associated with gradual onset and steady progres-sion through hoarseness to stridor during a period of 2 or 3 days. Viral laryngotracheobronchitis may be more difficult to differentiate, and, if diphtheria is suspected for epidemiologic or other reasons, laryngoscopy is indicated.

The ability of strains C. diphtheriae to produce toxin results from a nonlytic infection by one of a series of related bacte-riophages that contain a genetic sequence encoding the toxin. The phage integrates into specific sites present in C. diphtheriae and other Corynebacterium species. The presence of the phage is thought to confer a survival advantage to the bacterium by increasing the probability of transmission in a susceptible population; transmission may be facilitated by local tissue damage resulting from the toxin.43,44 The sequence of diphthe-ria toxin has been demonstrated to be highly conserved in C. diphtheriae strains, suggesting that immunologically important differences among the toxins produced by different strains are unlikely to occur.45 Once integrated, the tox gene is part of a multiple bacterial gene operon; other bacterial gene products in this operon are involved in the liberation and uptake of host iron.46 The entire operon is under the control of a repres-sor gene, dtxR, which in the presence of iron binds to and inhibits the tox gene; toxin is produced only under low-iron conditions.47

Diphtheria toxin is a polypeptide with a molecular weight of approximately 58,000 Da. The toxin is secreted as a proen-zyme, requiring enzymatic cleavage into two fragments (frag-ments A and B) to become active. Fragment B is responsible for attachment to and penetration of the host cell. Although nontoxic by itself, fragment B appears to be the antigen responsible for clinical immunity. The receptor domain of fragment B binds to a cell surface receptor, heparin-binding epidermal growth factor precursor,48 with CD9 as a corecep-tor.49 After receptor-mediated endocytosis and penetration of the cell, fragments A and B are detached.50 The released frag-ment A is the toxic moiety, and it acts by inhibiting protein synthesis, resulting in cell death.44 Unless cell penetration occurs, fragment A is inactive. Differences in the tissue distri-bution of the receptor and coreceptors may account for the differential effects of diphtheria toxin on different organs.51,52

The ability of tox gene–containing bacteriophages to infect nontoxigenic strains of C. diphtheriae provides a potential explanation for the fact that, during outbreaks of diphtheria, both toxin-producing and non–toxin-producing strains of the organism may be isolated on culture surveys. Some evidence suggests that the introduction of a toxin-producing strain of C. diphtheriae into a community may occasionally initiate an outbreak by transfer of phage to nontoxigenic strains of the organism carried in the respiratory tracts of community inhabitants, rather than a new strain being the responsible agent.53

On mucous membranes, the toxin causes local cellular destruction, and the accumulated debris and fibrin result in the characteristic membrane. More important, absorbed toxin is responsible for remote manifestations affecting various organs, including, for example, the myocardium, nervous system, and kidneys. Because the lethality of diphtheria is almost entirely determined by the organism’s toxin, clinical immunity depends primarily on the presence of antibodies to the toxin. In the presence of small amounts of formaldehyde, diphtheria toxin loses its attachment and enzymatic activities while retaining its immunogenicity, thus becoming a toxoid. This process is the basis of active immunization against diphtheria.

Certain cell wall antigens of C. diphtheriae are also thought to contribute to the pathogenesis of the disease in humans. The cell wall contains a heat-stable O antigen, which is found in all corynebacteria. The cell wall also contains K antigens, which are heat-labile proteins that differ among strains of C. diphtheriae and therefore permit categorization of the organ-ism into a number of types.54 The K antigens play two roles in relation to humans: first, they appear to be important in the establishment of infection, and second, they produce local



given to hasten clearance of the organism, prevent transmis-sion, and cease further production of diphtheria toxin.89 Before the availability of antibiotic therapy, convalescent car-riage of toxigenic organisms was a major problem. Up to 50% and 25% of patients continued to harbor the organism 2 and 4 weeks after onset, respectively. As late as 2 months after onset, reported carriage rates varied between 1% and 8%.3 Long-term convalescent carriers were often subjected to tonsil-lectomy, probably with some effect.90

Treatment with penicillin or erythromycin should be con-tinued for 2 weeks. On completion of treatment, patients should be cultured twice at least 24 hours apart to confirm elimination C. diphtheriae. Patients who continue to harbor the organism after treatment with either penicillin or erythro-mycin should receive an additional 10-day course of oral erythromycin, and specimens for follow-up cultures should be obtained on completion of the course.89 Although treat-ment with penicillin or erythromycin has no apparent effect on the clinical course of the disease, in most instances the organism can no longer be recovered on culture within a week of therapy and subsequent convalescent carriage is thus uncommon.

EPIDEMIOLOGYIncidence and Prevalence DataActive immunization of children with diphtheria toxoid has markedly altered the epidemiology of diphtheria, reducing diphtheria to extremely low levels in both developed countries and developing countries that have sustainable and well-implemented vaccination programs. However, diphtheria continues to produce substantial childhood morbidity and mortality in developing countries with incompletely imple-mented childhood immunization programs.91,92

From 1980 to 2014, only 57 cases of respiratory diphtheria were reported in the United States.93–101 The last case in the United States was reported in 2014 in a 17-year-old white female resident of Ohio.101 However, the isolated organism C. diphtheriae was nontoxigenic. The patient was fully immu-nized. No other family member or close contact was ill.

The decline of reported cases in the United States was abrupt partially because cutaneous diphtheria ceased to be nationally notifiable in 1980 (Fig. 19.1). However, improved childhood immunization in Mexico and other developing countries as part of the World Health Organization (WHO) Expanded Programme on Immunization (EPI) beginning in the late 1970s is likely to have contributed to improved diph-theria control in the United States by reducing importations of toxigenic strains. In the mid-1990s, with so little disease reported in the United States, it seemed likely that toxigenic strains of C. diphtheriae were no longer circulating in this country.93 However, in 1996, surveillance revealed widespread circulation of the organism in one American Indian commu-nity in the Northern Plains.102 Similarly, although recognized cases of diphtheria remain rare, endemic transmission of C. diphtheriae has been documented in some native communities in Canada.103–105 Strains from the United States and Canada were assayed by ribotyping and multilocus enzyme electro-phoresis and found to be closely related to strains that circu-lated in the same areas during the 1970s and 1980s, suggesting ongoing endemic circulation.66,88 Circulation has also been reported among the aboriginal population in central Austra-lia.106 The common denominator in these communities is likely to be poverty and crowding.

In temperate climates, respiratory diphtheria occurs year-round but most often during colder months, probably because of the close contact of children indoors. In tropical climates,

Nasal diphtheria may be difficult to distinguish from many other causes of nasal discharge and accordingly is most likely to be suspected if the patient has been exposed to diphtheria, such as during an outbreak. Suspicion should be heightened if a serosanguineous discharge is present and if the upper lip is ulcerated. However, the latter also occurs with streptococcal infections. Any cutaneous or mucous membrane lesions at other sites should be considered suspicious if a membrane is noted.

The risk of complications and mortality from diphtheria are inversely related to the promptness of diagnosis and treat-ment. Thus, it is critical that the diagnosis be considered, appropriate clinical specimens be obtained, and a decision made regarding administration of antitoxin as early as possi-ble in the course of illness. When diphtheria is suspected, treatment for the disease should be initiated immediately after bacteriologic specimens are obtained, without waiting for results. Delay, even for a few hours, may increase the risk of complications and death.

Swabs for culture should be obtained under direct visualiza-tion, preferably from the edge or beneath the edge of the mem-brane. Directly stained smears are usually grossly misleading even in experienced hands and should not be used. Swabs should be inoculated promptly onto tellurite-containing media and onto blood agar.68 Cultures should be incubated promptly and interpreted by an experienced microbiologist. Because not all C. diphtheriae recovered on culture are toxigenic, testing for toxin production must be performed. The modified Elek immu-noprecipitation test for detection of toxin is the standard assay, but it generally requires 24 to 48 hours, and more rapid approaches to toxin detection have been described.69 Many laboratories now use a polymerase chain reaction (PCR) assay for the detection of the tox gene.70–73 Although this assay can provide a rapid indication that an isolate may be toxigenic, in some isolates the tox gene is detected but is nonfunctional.74 For this reason, toxin production in PCR-positive isolates should be confirmed by an immunoprecipitation test. PCR can also be performed directly on clinical specimens.75 Real-time PCR assays that detect toxin genes associated with both C. diphthe-riae and C. ulcerans have been developed.76,77

Several approaches to typing of strains of C. diphtheriae as an adjunct to epidemiologic investigations have been devel-oped. During the 1960s, Saragea and Maximescu78 developed a system of phage typing and demonstrated considerable diver-sity of circulating strains in different countries. Subsequently, the usefulness of molecular typing methods was demonstrated in analysis of outbreak-related strains in Sweden79 and the United States.80 Since then, ribotyping,81 pulsed-field gel elec-trophoresis,81 and multilocus enzyme electrophoresis82 have been used for molecular subtyping, as has PCR–single-strand conformation polymorphism (SSCP) analysis.83 A rapid ribo-typing method using PCR-SSCP has been described.84 Ribotyp-ing has been used most extensively and standard nomenclature has been developed.85 Multilocus sequence typing also has been used and appears useful for discriminating reliably among strains of C. diphtheriae.86 Molecular methods have been used to characterize the dominant strains of C. diphtheriae associated with the outbreak in the former Soviet Union,81 and to document ongoing endemic circulation in certain commu-nities in the United States and Canada.66,87,88 However, these tests are only available in research laboratories.

TREATMENT AND PREVENTION WITH ANTIMICROBIALSAlthough diphtheria antitoxin is the mainstay of diphtheria therapy, penicillin or, alternatively, erythromycin should be



19

Significance as a Public Health ProblemIn the past, in the absence of immunization, most people acquired immunity to diphtheria as measured by the Schick test without experiencing clinical diphtheria. Transplacental antibody to diphtheria toxin is present at birth in most infants but declines to nonprotective levels during the second 6 months of life. Thereafter, the proportion of immune children (Schick-negative) in unimmunized populations gradually increases to 75% or more, presumably as a result of repeated subclinical infection with the organism.118

In the 21st century, it is difficult to comprehend what a major cause of morbidity and mortality diphtheria was in the past. Before 1900, the best data for the United States were from Massachusetts. From 1860 to 1897, death rates from diphtheria ranged between 46 and 196 per 100,000 popula-tion annually, with a median of 78, with the proportion of total deaths attributable to diphtheria ranging from 3% and 10% annually.119 By 1900, a considerable fall in the death rate had occurred and continued to decline from 40 to 15 per 100,000 over the next 20 years, presumably because of the therapeutic use of diphtheria antitoxin and, perhaps, other measures such as intubation. However, even in 1900, more than half as many deaths from diphtheria were recorded in the United States as from cancer.119 Several interesting and readable histories of diphtheria in the late 19th and early 20th centuries have been published.120–122

Excellent data on morbidity, mortality, and case-fatality rates for diphtheria were available for the Province of Ontario for 1880 to 1940 and for several Canadian cities for some of those years.123 Mortality from diphtheria exceeded 50 per 100,000 population in most years before the advent of diph-theria antitoxin. Mortality subsequently declined to approxi-mately 15 per 100,000 by World War I, although morbidity rates did not decline. With the widespread use of diphtheria toxoid vaccine beginning in the late 1920s in Canada, the disease nearly disappeared.124

At the beginning of the 20th century, diphtheria was a major cause of death of children in the United Kingdom. In 1934, the diphtheria mortality rate among children was 38.5 per 100,000. Widespread diphtheria immunization programs began there in 1940 and by 1944, it was reduced to 9.2 per 100,000, and by 1949 both morbidity and mortality were reduced more than 10-fold compared with the period from 1940 to 1941 (Fig. 19.2).125

Since the introduction of vaccination with diphtheria toxoid, a number of diphtheria outbreaks have occurred in

cutaneous diphtheria is more common and is unrelated to season.

Risk GroupsUnvaccinated or inadequately vaccinated preschool and school-age children are most often affected by respiratory diphtheria. Diphtheria is rare in infants younger than 6 months of age, presumably because of the presence of mater-nal antibody, and rare among adults, especially those living in urban areas, as a result of acquired immunity. Although no differences in diphtheria incidence were noted by sex in the prevaccine era, an increased risk of diphtheria among women was reported in several outbreaks among adults in the 1940s and subsequently; an increase in risk of diphtheria among women was observed in Russia and some of the other coun-tries of the former Soviet Union during the outbreaks that occurred there in the 1990s.64,107–111

Reservoirs of Infection and Modes of TransmissionHumans are the only natural host for C. diphtheriae. Transmis-sion is from person to person, most likely by intimate respira-tory and physical contact. The organism is reasonably hardy and has been isolated from the environment of persons infected with C. diphtheriae.112–115 Nonetheless, the occurrence of indirect transmission by airborne droplet nuclei, dust, or fomites has not been established. Evidence of outbreaks caused by contaminated milk and milk products has been reported.23,115,116 Cutaneous lesions appear to be important in transmission under poor social conditions.9,10,117

The precise microbial events responsible for the transmis-sion of diphtheria remain unclear. However, the molecular epidemiologic data showing clonal identity of bacteria in large numbers of infected people in the outbreaks in Seattle,80 Sweden,79 and Russia87 strongly suggest that direct spread of toxigenic bacteria from one individual to another is a major factor in large epidemics.

Figure 19.1. Diphtheria incidence in the United States, 1920–2014, and mortality rates, 1920–1980. Years in which no case was reported are plotted with an incidence rate of 0.0001 per 100,000 population. Because of the small number of diphtheria deaths since 1980, case fatality rates (CFRs) are unstable and are not shown on this graph. CFRs have varied widely since 1980 because of the small number of cases, but the overall CFR from 1980 to 2010 was 16%. (Data from the Centers for Disease Control and Prevention, Atlanta, GA.)

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Figure19.2. Diphtheria cases (solid line) and deaths (dashed line) in England and Wales, 1940–1949. (From Mortimer PP. The diph-theria vaccine debacle of 1940 that ushered in comprehensive child-hood immunization in the United Kingdom. Epidemiol Infect. 2011;139:487–493.)

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physicians fears about adverse events, the use of three doses of Td (diphtheria and tetanus toxoids–adult) instead of DTP (diphtheria, tetanus, pertussis) in the childhood immuniza-tion schedule, and the absence of an adult Td immunization program resulted in inadequate population immunity among children and adults. In addition, delayed recognition of cases and public health response, and changing social conditions facilitated spread once the outbreak began.111 In the Russian Federation, the emergence of an epidemic clone of C. diphthe-riae biotype gravis was demonstrated.82 The epidemic clone was present in Russia as early as 1985, and strains of this clonal group have been retrospectively identified in different geographic areas of Russia from 1985 to 1987.134 Many cases were also caused by biotype mitis strains as well, especially in the newly independent states of Central Asia, suggesting that microbial factors alone did not account for the epidemic.135 The Russian epidemic peaked between 1994 and 1995 and subsequently was brought under control by increasing immu-nization coverage with diphtheria toxoid among both chil-dren and adults (see later).64,111

Diphtheria toxoid has been included in the WHO’s EPI since its inception in 1974. In developing countries, the imple-mentation of the EPI has led to dramatic falls in the global number of reported cases of diphtheria since 1980; however, marked disparities remain in reported rates between countries. Some countries have achieved control of diphtheria compa-rable to that seen in highly developed countries. In others, disease rates have fallen dramatically but sporadic outbreaks still occur, for example, Thailand,136 India,137–139 Brazil,140 Indonesia,141 and Laos,142 which have recent evidence of wide-spread circulation of toxigenic strains. Low vaccination cover-age rates and population immunity were reported in the affected areas in these countries.

Before the WHO EPI began, it was estimated that close to a million cases of diphtheria occurred annually in the Third World, with 50,000 to 60,000 deaths.143 From 1980 to 2013, reported cases of diphtheria globally decreased from 97,774 to 4680 in 2013 with control of the outbreak in the former Soviet Union. Approximately 87% of cases worldwide in 2013 were reported from the WHO Southeast Asian region (Fig. 19.4); 77% of cases in this region were reported from India.144

Under the EPI, the goal was to achieve 90% or higher immunization rates in 1-year-old children by the year 2000. By this time, it was estimated that the proportion who had received three doses of DTP vaccine (DTP3) had risen from negligible levels in the early 1970s to 81% worldwide, with Africa being the lowest at approximately 55%.145 By 2013, global coverage improved to 84% while 79% of the countries of the African region reported DTP3 coverage of 80% or more by 1 year of age.144 Some of the regional differences in these data no doubt reflect differences in either the capacity or quality of surveillance in member countries.

PASSIVE IMMUNIZATIONThe history of the development of diphtheria antitoxin was reviewed in detail by Andrewes and colleagues.3 In brief, in 1888 Roux and Yersin reported their observation that bacteria-free filtrates of broth cultures of C. diphtheriae, when injected into animals, produced all the manifestations of diphtheria except for the membranous local lesions.146 In rapid succes-sion, other advances followed. von Behring showed that inactivated cultures of the organism injected into animals subsequently rendered them protected against living cul-tures.147 Ultimately, von Behring demonstrated the transfer of protection from an immunized animal to another unimmu-nized one by serum, which he named antitoxin. Diphtheria antitoxin was first given to a child in 1891, and antitoxin was

Figure19.3. Reported cases of diphtheria, by year, in the Soviet Union (1965–1990) and in the newly independent states of the former Soviet Union (1991–2013).

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industrial countries. During World War II, a major outbreak spread throughout western Europe with well over 1 million cases reported.126,127 The outbreaks spread from Europe to North America. A major outbreak affecting nearly 1% of the population of Halifax, Nova Scotia, during the winter of 1940–1941 was linked to disease imported by Norwegian sailors.128 Another outbreak occurred in Alabama in 1943 among German prisoners of war.129

By the late 1950s, the incidence of diphtheria was markedly reduced in the United States, but disease continued to occur in some other areas. From 1959 to 1970, 5048 cases of diph-theria were reported in the United States, with the highest incidence rates reported in the southeast, south central, and northern plains states. Incidence rates were 20-fold higher for Native Americans and sevenfold higher for blacks than for whites.130

Diphtheria incidence continued to decline (see Fig. 19.1), and from 1971 to 1981, 853 noncutaneous and 435 cutaneous cases were reported in the United States.131 Incidence rates exceeded 1 per million population in South Dakota, New Mexico, Alaska, Washington, Arizona, and Montana, and inci-dence rates were 100-fold greater for Native Americans than for whites and blacks.131 During this period, there were seven outbreaks with 15 or more cases in the United States.131 From 1972 to 1982, a large outbreak of predominantly cutaneous diphtheria occurred among residents of Skid Road in Seattle, Washington.10,80 The Seattle outbreak and most of the other outbreaks from 1969 to 1980 were caused by toxigenic strains of the intermedius biotype, which had previously been uncom-mon; clonality of these strains was suggested by molecular epidemiologic studies of strains from outbreaks in Seattle80 and the southwestern states.132

Although diphtheria has become a rare disease in most developed countries, a major epidemic of it began in the Russian Federation in 1990 and subsequently spread through-out the countries of the former Soviet Union (Fig. 19.3), with more than 157,000 cases and 5000 deaths reported between 1990 and 1998.111 A compendium summarizing the knowl-edge gained from this outbreak has been published.133 Although the cause of the epidemic was uncertain, it was multifactorial. Contributing factors included decline in childhood vaccination acceptance and coverage, exaggerated



19

difficulty in identifying a supplier and maintaining a supply for domestic use.151,152 As of January 6, 1997, licensed diph-theria antitoxin with a valid expiration date was no longer available in the United States, and there was no manufacturer proposed to produce it. However, for treatment of the disease in the United States, the Centers for Disease Control and Prevention has a supply of antitoxin that can be distributed for treatment under an investigational new drug protocol.153 This antitoxin is comparable to the prior U.S. product and may be requested by calling 770-488-7100.

Novel approaches to passive immunity could include the commercial development of human monoclonal antibodies to diphtheria toxin or the development of recombinant modi-fied diphtheria toxin receptor molecules to bind diphtheria toxin.154,155 A neutralizing monoclonal antibody of human origin has been developed which completely protected guinea pigs from lethal challenge in an in vivo assay. The monoclonal antibody binds to the receptor-binding domain of diphtheria toxin and blocks the toxin from binding the receptor.156

Postexposure Use of Antitoxin and ToxoidThe value of antitoxin in postexposure prophylaxis is dubious. Theoretically, it should be useful in preventing the establish-ment of infection in exposed, susceptible people because the toxin plays a role in local invasiveness. However, there is no acceptable clinical evidence of prophylactic efficacy; all that exist are anecdotes and small, uncontrolled series of experi-ments.3 Even if it were effective, antitoxin would be of little use in controlling community outbreaks, because asymptom-atic carriers, rather than persons with overt disease, are usually the major source of transmission.157 For these reasons,

commercially produced in Germany in 1892. The use of horses for the production of antitoxin began in 1894 and was widespread within a few years. The lack of regulated standards for the production of equine diphtheria antitoxin resulted in the release of contaminated or counterfeit antisera and con-tributed to the development of the predecessors of the present Center for Biologics Evaluation and Research of the U.S. Food and Drug Administration (FDA).148–150

Equine diphtheria antitoxin continues to be used to date. The product is prepared by hyperimmunizing horses with diphtheria toxoid and toxin.149 To diminish reactivity from horse serum, current preparations are semipurified by tech-niques that concentrate immunoglobulin G and remove as much extraneous protein as possible. There must be at least 500 units of antitoxin per milliliter, and sterility is attained by microfiltration. A cresol derivative is added as a preservative.

Diphtheria antitoxin is used for the treatment of diphtheria and occasionally for prevention in exposed persons. Its thera-peutic efficacy is well established, although it is in no way a substitute for prior active immunization with diphtheria toxoid. No antiserum or hyperimmunoglobulin of human origin is currently available.

Globally, the production and supply of equine antitoxin for human therapeutic use has become increasingly problem-atic. Almost all industrialized countries that traditionally manufactured and supplied antitoxin have ceased production. Unavailability of an antitoxin supply increases the likelihood of mortality, as highlighted by shortages during the epidemic in the newly independent states of the former Soviet Union. With low demand for the product, many manufacturers have left the market, so only a few manufacturers supply diphtheria antitoxin to other countries, many of which have reported

Figure19.4. Reported cases of diphtheria, by year and region, 1980–2013. AFR, African region; AMR, American region; EMR, European region; EUR, European region; SEAR, Southeast Asia region; WPR, Western Pacific region. (From World Health Organization, Department of Vaccines and Biologicals, Vaccine-Preventable Diseases: Monitoring System 2014 Global Summary. http://apps.who.int/immunization_monitoring/globalsummary/timeseries/tsincidencediphtheria.html.)

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http://apps.who.int/immunization_monitoring/globalsummary/timeseries/tsincidencediphtheria.html



name has since been replaced in English usage with the term toxoid. For primary immunization, the toxin-antitoxin prepa-ration was gradually replaced by toxoid in the United States and Canada during the next 15 years, and elsewhere thereafter. In 1926, Glenny and coworkers165 found that alum-precipitated toxoid was more immunogenic, and by the mid-1940s, diph-theria toxoid was combined with tetanus toxoid and pertussis vaccine as diphtheria and tetanus toxoids and whole-cell per-tussis vaccine. Adsorption of all three onto an aluminum salt followed shortly thereafter. It is clear that the immunogenicity of diphtheria toxoid, as well as that of tetanus toxoid, is enhanced by the adjuvant effects of both pertussis vaccine and the aluminum salt.166–168 In recent years, diphtheria and tetanus toxoids with acellular pertussis components (DTaP) have been licensed, and various other combinations of DTaP with Hib vaccine, inactivated poliovirus vaccine, and hepatitis B vaccine have been developed.169 Combination vaccines have been shown to be as comparably immunogenic as the mon-ovalent preparations.

Vaccine ConstituentsA preservative to prevent antimicrobial growth is required when diphtheria toxoid is dispensed in multidose vials. Thi-merosal, a preservative containing ethyl mercury, has been used in vaccines and biologics for this purpose since the 1930s.170 Some diphtheria toxoid–containing vaccines con-taining only trace (<1 µg of mercury) or no thimerosal are available in single-dose preparations (single-dose vials or pre-filled syringes). Diphtheria toxoid is adsorbed onto an adju-vant (most commonly aluminum hydroxide or aluminum phosphate) to improve the immunogenicity of the vaccine. Only adjuvanted diphtheria toxoids are available in the United States.

Manufacture of VaccineDiphtheria toxoid is produced worldwide in a standard fashion; in the United States, production and testing proce-dures are specified in the Code of Federal Regulations. Specifi-cally, a strain of C. diphtheriae that is known to produce large amounts of toxin (such as the Park Williams 8 strain) is grown in a liquid medium conducive to toxin production. After appropriate incubation, sterilization is achieved by centrifuga-tion and filtration. After ascertainment of potency, the filtrate is incubated with formalin for conversion to toxoid. The product is then further purified and concentrated to achieve the necessary dosage. It is adsorbed onto an aluminum salt, usually aluminum hydroxide or aluminum phosphate. After each step, appropriate tests for potency and sterility are con-ducted. Toxoid concentration is ascertained by determining the content of flocculating units (Lf) in established fashion; 1 Lf is the amount of toxoid that flocculates 1 unit of a stan-dard reference diphtheria antitoxin. The purity of diphtheria toxoids in vaccines currently licensed in the United States is usually at least 1500 Lf/mg nondialyzable nitrogen; WHO rec-ommends a similar standard. Toxoid potency is determined by assays, with different tests currently required by WHO, the European Pharmacopoeia, and the FDA.148,171,172 Although there are ongoing efforts to harmonize potency testing require-ments globally, no single approach has yet been universally adopted.

ProducersDiphtheria toxoid is produced both by large multinational vaccine companies and by developing country manufacturers, many of which produce vaccine only for domestic use. A 1995

antitoxin is not recommended for exposed, susceptible persons, particularly in view of the high rates of subsequent serum sickness and occasional anaphylaxis. The preferred treatment for exposed, unimmunized, asymptomatic persons is to obtain a throat culture, begin immunization with a prepa-ration containing diphtheria toxoid that is appropriate for age, and institute prophylaxis with erythromycin or penicillin for 7 days, during which time the patient must be kept under surveillance for development of symptoms.89

USE OF ANTITOXIN FOR TREATMENT OF DIPHTHERIAMany studies have demonstrated that therapy with antitoxin is efficacious in reducing mortality from diphtheria primarily by preventing cardiovascular toxicity.4,158 However, only a single controlled therapeutic trial is discussed in the litera-ture.159,160 This nonblinded trial consisted of treating all patients admitted on alternate days with antitoxin and com-paring their outcomes with those of patients admitted on nontreatment days. Eight (3.3%) of 242 patients treated with antitoxin died, compared with 30 (12.2%) of 245 control subjects.

In addition, many observations of the direct relationship between mortality and the day of disease when antitoxin was administered provide ample evidence of its efficacy. For example, among 3558 patients observed by Ker,158 320 cases of paralysis occurred. There was a strong direct relationship between the frequency of postdiphtheritic paralysis and the number of days between onset of illness and administration of antitoxin. Only 4.8% of 1168 patients developed paralysis when antitoxin was administered no later than the second day of illness, in contrast to 12.1% of 1375 patients who received antitoxin on the fourth day of the disease or later.

Antitoxin is given intramuscularly or intravenously; many authorities prefer the intravenous route for at least part of the dose because a therapeutic blood level can be reached more rapidly.161 The entire therapeutic dose should be administered at one time, and the amount of antitoxin recommended varies between 20,000 and 100,000 units. Larger amounts are recom-mended for persons with extensive local lesions, because the amount of toxin produced depends on the size of the mem-brane. Furthermore, the longer the interval since onset, the higher should be the dose of antitoxin. Toxin that has already entered host cells is unaffected by antitoxin.

ACTIVE IMMUNIZATIONHistory of Vaccine DevelopmentAfter the discovery of diphtheria toxin and the development of antitoxin in the 19th century, the first successful approach to active immunization was the use of balanced mixtures of toxin and antitoxin, which successfully immunized both animals and humans after injection.162,163 The combination preparation, toxin-antitoxin, was rapidly accepted as an active immunizing agent. It was widely used in the United States beginning in 1914, and was found to protect approximately 85% of recipients.164 There is little question that the toxin-antitoxin preparation developed by von Behring created active immunity against diphtheria, on the basis of the results of Schick testing and clinical observation, despite the absence of well-controlled studies.3

In the early 1920s, Ramon treated diphtheria toxin with small amounts of formalin and found that the product retained most of its immunizing capacity while losing its toxic properties.6 Ramon dubbed this preparation anatoxine; this



192005, formulations of tetanus and diphtheria toxoids with acellular pertussis vaccine (Tdap) have been licensed in the United States for use in adolescents and adults. Boostrix (Glax-oSmithKline) is currently licensed for use in persons 10 years of age and older, and Adacel (Sanofi Pasteur) is licensed for use in persons 11 to 64 years of age. These vaccines are licensed for use as a single booster vaccination in persons who have previously received a primary series of DTP or DTaP. A single dose of Tdap is recommended by the ACIP in the United States for persons aged 11 years and older, with the preferred timing at 11 to 12 years of age.178 A dose of Tdap is recommended for women during each pregnancy to provide maternal antibodies to their newborn for added protection against pertussis until they are eligible to receive their first dose of DTaP.179

Dosage and RouteAll products currently in use in the United States are administered as a 0.5-mL dose. Preparations containing diph-theria toxoid should always be injected intramuscularly, not subcutaneously.

Vaccine StabilityExpiration dates for diphtheria toxoid are established through the licensing process for each vaccine by national authorities. Preparations containing diphtheria toxoid should be stored at refrigerator temperatures (2°C to 8°C) but not frozen. If vaccine has been frozen, it should be discarded.

Immunogenicity of VaccineSeveral laboratory assays for diphtheria antitoxin are available. Vero cell neutralization assays are highly accurate but techni-cally cumbersome and are available in only a few research laboratories.180 Standard enzyme immunoassays are widely available and technically less demanding; these assays gener-ally correlate with results from neutralization assays at concentrations greater than 0.01 IU/mL.181 Double-antigen enzyme-linked immunosorbent assay (ELISA), double-antigen delayed time-resolved fluorescence immunoassays, and toxin-binding inhibition tests, which are more accurate than stan-dard enzyme immunoassays but technically less demanding than Vero cell neutralization, have been developed.182,183

Maternal antitoxin levels do affect the immune response of infants. Diphtheria antitoxin levels greater than 0.1 IU/mL inhibit the response to active immunization, but no effect is seen at levels of less than 0.02 IU/mL.184,185 This is more likely to be of significance in areas where C. diphtheriae continues to circulate, resulting in high levels of antibody in mothers and their infants. However, it appears that high maternal antibody titers suppress, but do not prevent, adequate responses of infants to two doses of vaccine, and after the third dose the suppressive effect is gone.186,187 The half-life of diphtheria anti-toxin has been estimated to be 30 days.188

After three doses of diphtheria toxoid, nearly all infants develop diphtheria titers greater than 0.01 IU/mL.189 Geomet-ric mean titers vary among vaccine preparations, with some DTaP products producing significantly lower geometric mean titers than those observed after vaccination with DTP174; however, these differences are unlikely to be clinically signifi-cant. When the toxoid is used for primary immunization of adults, data suggest that nearly all adults develop diphtheria antitoxin titers greater than 0.01 IU/mL after administration of three doses of diphtheria toxoid, and that most develop titers greater than 0.1 IU/mL.190

Vaccination with protein conjugate vaccines containing diphtheria toxoid may result in a booster response to the

assessment of global DTP manufacturing capacity reported DTP production by 63 manufacturers in 46 countries. At that time, it was estimated that approximately two-thirds of chil-dren received DTP that was manufactured in their own country, and that more than one-half of the global DTP supply came from developing country manufacturers.173 In 2006, it was estimated that more than 500 million doses of DTP were produced globally, with many manufacturers producing vaccine for domestic use only. More than 100 million doses of DTaP are produced as well, with major production by Sanofi Pasteur and GlaxoSmithKline.

Preparations Available, Including CombinationsCurrently in the United States, diphtheria toxoid is available in combination with tetanus toxoid (DT [diphtheria and tetanus toxoids–pediatric], Td) and in combination with tetanus toxoid and acellular pertussis vaccine (DTaP), as well as in other combination vaccines including DTaP; additional combination vaccines are available in Europe, Canada, and Australia that are not licensed for use in the United States. Globally, diphtheria toxoid continues to be used in combina-tion with tetanus toxoid and whole-cell pertussis vaccine (DTP) as well as in other combinations including DTP. The product is available only in adsorbed form in the United States.

Since September 2011, DTaP vaccines from two manufac-turers are marketed for use in infants in the United States: Infanrix (manufactured by GlaxoSmithKline Biologicals and distributed by GlaxoSmithKline) and Daptacel (manufactured by Aventis Pasteur Ltd., and distributed by Sanofi Pasteur). Two pentavalent combination vaccines—a combined DTaP (Infanrix), hepatitis B vaccine, and inactivated polio vaccine (GlaxoSmithKline) and a combined DTaP, Hib conjugate vaccine, and inactivated polio vaccine (Pentacel, Sanofi Pasteur, Ltd.)—are available for use at 2, 4, and 6 months of age; Pentacel is also licensed for use for the fourth dose of the series. A DTaP-inactivated polio vaccine combination, KINRIX, is licensed and marketed by GlaxoSmithKline Biologicals for use as the fifth dose of the DTaP series at 4 to 6 years of age. Another DTaP-inactivated polio vaccine combination, Quadra-cel, was licensed and marketed by Sanofi Pasteur Limited for active immunization against DTP and poliomyelitis in the United States. A single dose of Quadracel is licensed for use in children 4 through 6 years of age as a fifth dose in the DTaP vaccination series, and as a fourth or fifth dose in the inacti-vated poliovirus vaccination (IPV) series, in children who have received 4 doses of Pentacel and/or Daptacel vaccine.

The amounts of diphtheria toxoid in the DTaP vaccines currently licensed in the United States range from 6.7 to 25 Lf/0.5-mL dose. They provide levels of serum antitoxin that are considerably lower than those seen after receipt of whole-cell DTP, probably reflecting the adjuvant effect of the whole-cell pertussis component.174,175 However, the lower antitoxin levels induced by vaccination with DTaP are probably of no clinical consequence, being manyfold higher than protective levels.169 For routine immunization of children, five doses are recommended (at 2, 4, 6, and 15 to 18 months of age and at school entry before the seventh birthday).176 The fourth dose should be administered at least 6 months after the third dose.177

Combined adult formulation tetanus and diphtheria toxoids (Td) are licensed in the United States for use in persons 7 years of age and older. These vaccines are licensed for primary vaccination as a three-dose series in previously unvac-cinated persons 7 years of age and older, and as a decennial booster for use in adolescents and adults. These products contain reduced amounts of diphtheria toxoid (<2 Lf). Since



during the next few months. Among those immunized, the monthly incidence of diphtheria fell to 24.5 per 100,000 pop-ulation, about one-seventh of the rate in the unimmunized children during that same period (168.9 per 100,000). In Britain in 1943, the rate of clinical diphtheria among the unimmunized was 3.5 times that among the immunized, and mortality was 25-fold greater.127 In an outbreak in Elgin, Texas, in 1970, only two of 205 fully immunized, exposed elemen-tary schoolchildren acquired the disease.205 In contrast, among 97 children who had received inadequate or no immuniza-tion, a 13% attack rate occurred.

In a household study during a diphtheria outbreak in San Antonio, Texas, in 1970, vaccine efficacy was estimated at only 54%.206 However, because index cases were included and denominators of exposed individuals were unknown, the data are difficult to interpret. Furthermore, any differences in attack rates between immunized and nonimmunized persons might have been blunted by the institution of antibiotic therapy in all members of the household on recognition of a case. Thus, the apparent efficacy of 54% is probably low. In an outbreak in Yemen, the protective efficacy of diphtheria toxoid was determined to be 87% by the case-control method.116

The effectiveness of Russian-manufactured diphtheria toxoid was evaluated in several case-control studies during the epidemic in the former Soviet Union. Three or more doses of diphtheria toxoid were demonstrated to be highly effective in prevention of diphtheria among children younger than 15 years in a preliminary study in Ukraine in 1992 and a subse-quent study performed in Moscow in 1993. In Ukraine, the effectiveness of three or more doses was 98.2% (95% confi-dence interval [CI], 90.3% to 99.9%).207 In Moscow, the effec-tiveness of three or more doses was 96.9% (95% CI, 94.3% to 98.4%), increasing to 99.0% for five or more doses (95% CI, 97.7% to 99.6%).208 In addition, administration of a booster dose of diphtheria toxoid within 2 years was shown to decrease risk of diphtheria among children 6 to 8 years of age com-pared with those who had received the last dose 3 to 4, or 5 to 7 years previously.209 Among adults in the Russian Federa-tion, the effectiveness of three or more doses compared with no doses was 70% (95% CI, 10% to 90%).210 Similarly, recent vaccination also was found to be highly effective among adults in Ukraine.211

Thus, it appears that the effectiveness of diphtheria toxoid is high but not 100%. However, most reports indicate that the disease in previously immunized individuals is milder and less likely to be fatal.130,131,205,212–214 In Britain in 1943, case-fatality rates in unimmunized children were more than seven-fold greater than rates in those who had been immunized (6.4% versus 0.9%).127 The failure to protect 100% of indi-viduals on exposure indicates the importance of herd immu-nity in the disappearance of diphtheria from developed countries.215

Duration of Immunity and ProtectionBoth the diphtheria toxoid formulation and the schedule of administration affect the level of diphtheria antitoxin achieved and the duration of protection. Globally, various schedules for primary immunization of infants are used, but after three doses of diphtheria toxoid, most children achieve antitoxin titers greater than the minimally protective level.216 However, in the absence of ongoing exposure, immunity wanes over time, requiring booster doses of diphtheria toxoid to maintain protective antitoxin levels. Longitudinal studies indicate that after a period of rapid decline of antitoxin levels, there is a prolonged, slower decline, presumably reflecting the initially activated immune system and half-life of immunoglobulin, followed by a sustained period of less active production of

carrier protein in persons who have previously received diph-theria toxoid.191 One of the tetravalent meningococcal polysac-charide diphtheria toxoid conjugate vaccines currently licensed in the United States (Menactra, Sanofi Pasteur) contains approximately six times as much diphtheria toxoid as is con-tained in the adult formulations of Td vaccine. Simultaneous administration of Td and Menactra resulted in much higher geometric mean titers of diphtheria antitoxin than did Td (120.0 IU/mL compared with 8.4 IU/mL); consistent with the increase in diphtheria toxoid content, Menactra alone was also substantially more immunogenic than Td alone (46.5 IU/mL compared with 8.4 IU/mL).192 There is also cross-reactivity between diphtheria toxoid and CRM197 in protein conjugate vaccines; the other tetravalent meningococcal polysaccharide conjugate vaccine licensed in the United States, Menveo (Novartis Vaccines and Diagnostics), uses CRM197 as the protein carrier. Children receiving meningococcal serogroup C-CRM197 vaccines develop higher diphtheria antitoxin levels than are seen in children who did not receive the vaccine.193,194 Lack of baseline immunity to diphtheria may result in poor antibody responses to vaccines conjugated to CRM197.195 Although immunologic interference is a potential concern with simultaneous administration of diphtheria toxoid with diphtheria toxoid or CRM197-containing protein conjugate vaccines,196–198 experience to date does not suggest that the immunogenicity of diphtheria toxoid is adversely affected by simultaneous administration with these vaccines.

Correlates of ProtectionSeveral lines of evidence suggest that persons with diphtheria antitoxin levels of less than 0.01 IU/mL should be considered susceptible. Ipsen reported results of studies in which rabbits were administered antitoxin and then challenged with intra-venously administered diphtheria toxin; rabbits with a serum level of 0.01 IU/mL were almost completely protected from death with the standard lethal dose.199 However, higher doses of toxin required higher serum antitoxin levels for equivalent protection. On the basis of studies of diphtheria antitoxin levels early in the course of disease, persons with diphtheria antitoxin levels of less than 0.01 IU/mL appear to be highly susceptible to disease, and higher levels are generally associ-ated with progressively less-severe symptoms.199–202 Probably no level of circulating antitoxin confers absolute protection; Ipsen reported two cases of fatal diphtheria in patients with antitoxin levels above 30 IU/mL the day after onset of symp-toms.199 Historically, clinical diphtheria was rare among persons with a negative Schick test; the minimal serum anti-toxin level associated with a negative Schick test was approxi-mately 0.005 IU/mL.203 Overall, the data allow some general conclusions regarding protective levels in most circumstances. An antitoxin level of 0.01 IU/mL is the lowest level providing some degree of protection, and 0.1 IU/mL is considered a protective level of circulating antitoxin. Levels of 1.0 IU/mL and greater are associated with long-term protection.204

Efficacy and Effectiveness of VaccineNo controlled clinical trial of the efficacy of the toxoid in preventing diphtheria has ever been conducted. There is, however, strong evidence from observational studies to support the effectiveness of vaccination. Some evidence of the protective efficacy of diphtheria toxoid is provided by observa-tions during the Halifax epidemic.128 During the course of this outbreak, an intense effort was made to administer diphtheria toxoid to previously unimmunized individuals, and the sub-sequent incidence of diphtheria in these children was com-pared with the incidence in the unimmunized population



19convalescent phase of illness because clinical infection does not always induce adequate levels of diphtheria antitoxin. However, vaccination after onset of disease has no role in treatment of diphtheria; diphtheria patients should be promptly treated with diphtheria antitoxin (see “Treatment and prevention with Antimicrobials” earlier).

SafetyCommon Adverse Reactions. Extensive data on adverse reactions after administration of currently available prepara-tions of diphtheria toxoid, adsorbed, are not available because the toxoid is usually administered in combination with tetanus toxoid and, in children, with pertussis vaccine as well. When it is given in combination with pertussis vaccine, local reactions often are ascribed to the pertussis-containing com-ponent. In several large clinical trials, the reactogenicity of DT was compared with that of DTaP for primary vaccination of infants. In general, the frequencies of reported common sys-temic symptoms (temperature of 38°C or higher, crying for 1 hour or longer, irritability, drowsiness, loss of appetite, vomit-ing) and local reactions (redness, swelling, tenderness) after vaccination with DT or DTaP were comparable.230–232 In clini-cal trials in Sweden and Italy, DT vaccines containing 15 or 25 Lf of diphtheria toxoid and 3.75 or 10 Lf of tetanus toxoid, respectively, were given to more than 7000 infants. The fre-quency of temperature of 38°C or higher after any vaccine dose was 35% in the Swedish trial and 9% in the Italian study. Other common systemic symptoms occurred with similar fre-quencies in the two studies: crying for 1 hour or longer in 5% and 6% of infants, irritability in 67% and 55% of infants, drowsiness in 54% and 43% of infants, loss of appetite in 22% and 26% of infants, and vomiting in 15% and 9% of infants. Redness and tenderness after any vaccine dose were reported in 42% and 22% of infants in the Swedish trial, respectively, and in 19% and 9% of infants in the Italian study, respectively. The frequencies of marked redness or swelling were substan-tially lower in both studies, with redness and swelling of 2 cm or more reported in only 4% and 6% of infants in the Swedish trial, respectively.230,231,233 The frequency of adverse reactions after DT increased with increasing dose number.232,234

Available data suggest that both diphtheria and tetanus toxoids contribute to the reactogenicity of Td and DT. Among Swedish medical personnel with a history of receipt of previ-ous primary immunization in childhood, adverse events (local tenderness and swelling >5 cm, or general discomfort) were reported by 11% of those who received 2.5 Lf of diphtheria toxoid, compared with 20% of those who received 2.5 Lf of diphtheria toxoid combined with 0.75 Lf of tetanus toxoid, documenting the additive effects of the two toxoids.235 Data from several controlled studies suggest that fever and local reactions are more common after administration of Td than after tetanus toxoid alone.236,237

In some populations, large numbers of previously primed persons develop local reactions and fever in response to diph-theria toxoid, even at low dosages. In a small study of Israeli military recruits who had been previously vaccinated in child-hood, mild to moderate pain at the injection site was reported by 38% and severe pain by 20% after receipt of a booster dose of 2 Lf diphtheria toxoid without tetanus toxoid; limita-tion of abduction was reported by 8%. Systemic symptoms of mild to moderate or severe weakness were reported by 24% and 9%, respectively, and a temperature of 38°C or higher was reported by a single subject (<1%).238 Similarly, a booster dose of 1.5 Lf was administered to 215 university students with prevaccination diphtheria antitoxin levels of less than 0.1 IU/mL. Eight percent reported tenderness at the injection site, and 13% reported pain with abduction, which

immunoglobulin.217,218 Both the four-dose schedule used in the United States, with 15 Lf doses at 2, 4, 6, and 15 months of age, and the three-dose schedule used in Sweden, Denmark, and Norway, administering 25 Lf doses at 3, 5, and 12 months of age, resulted in geometric mean levels well in excess of the minimally protective level at 48 months of age.219 Similar geometric mean levels were found 23 months after dose three was administered as DT (pediatric diphtheria and tetanus toxoids), DTP, or DTaP, with varying diphtheria toxoid con-tents in a two-, four-, and six-dose schedule.218 In 1990, the United Kingdom moved to an accelerated schedule, adminis-tering DTP at 2, 3, and 4 months instead of at 3, 5, and 9 months of age. Although postvaccination geometric mean concentrations of diphtheria antitoxin were lower among chil-dren vaccinated on the accelerated schedule, geometric mean antitoxin levels did not differ at age 4 years among children who completed the series at 8 to 13 months, 6 to 7 months, or before 6 months of age, suggesting that adequate protection would be maintained until administration of the preschool booster dose.220–222

Although various schedules for primary immunization appear to provide adequate protection from diphtheria in the early years of life, in the absence of a booster dose at 4 to 6 years, protection may not be maintained throughout the school-age years. In Sweden, the first booster dose after the primary series is not administered until age 10 years, resulting in lower levels of antitoxin among children 5 to 9 years of age than is observed in countries administering a preschool-age booster.223 In one study, 12% of 10-year-old children had diphtheria antitoxin levels below 0.01 IU/mL before receipt of a booster dose.224 In the Soviet Union, the immunization schedule was changed in 1986, delaying the age 6 (years) booster dose to age 9 years. During the diphtheria outbreak in Russia in the 1990s, receipt of the booster dose at 6 to 8 years of age was found to decrease the risk of diphtheria in this age group.209 In countries with longstanding childhood immunization programs, adults who have neither been exposed to diphtheria nor received booster doses of diphtheria toxoid may become susceptible to diphtheria as a result of waning immunity.216 During the outbreak in the former Soviet Union, waning of immunity was thought to contribute to the high incidence rate observed among adults. A large proportion of the population of adults, although seronegative, were previ-ously primed by prior immunization or infection with toxi-genic C. diphtheriae, as evidenced by development of protective titers after a single booster dose of toxoid.225–228 Although the immunization histories of the adult patients were difficult to ascertain, the overall population data suggested that many probably had been immune but lost immunity over time. With implementation of booster vaccination for all age groups, the outbreak came under control.

The experience of this massive epidemic strongly suggests that sustaining high immunization coverage with a primary series of diphtheria toxoid among infants and administering booster doses at school entry and subsequently throughout life are important for maintenance of population immunity.114 WHO now recommends that people living in low-endemic or nonendemic areas should receive booster doses of diphtheria and tetanus toxoids approximately 10 years after completing the primary series, and subsequently every 10 years through-out life.229

Postexposure Prophylaxis and Therapeutic VaccinationThe immunization status of close contacts of diphtheria cases should be assessed, and any contacts found to not be fully up to date with diphtheria toxoid immunization should be vac-cinated.90 Diphtheria patients should be immunized in the



percent of children who had been primed with DT reported redness, 56% reported swelling, and 47% reported itching, compared with 23%, 15%, and 21%, respectively, among those who had received DTP.246 In contrast, local reactions did not differ among children who had received adsorbed DT for the primary series when they were boosted with either adsorbed or nonadsorbed DT.247,248

Although local injection site reactions are common, only a small proportion of these reactions are clinically significant. A study in the Vaccine Safety Datalink found a rate of medically attended local reactions after Td of 3.6 per 10,000 among persons 9 to 25 years of age. Although infection is an unlikely cause of injection site swelling after vaccination, persons with medically attended local reactions were frequently prescribed antibiotics for cellulitis.249 A similar rate of medically attended local reactions has been reported after Tdap.250 Because admin-istration of the U.S.-licensed tetravalent meningococcal con-jugate vaccine Menactra (Sanofi Pasteur) contains a relatively large amount of diphtheria toxoid and may produce a high level of diphtheria antitoxin in persons who have previously received childhood immunization with diphtheria toxoid–containing vaccines, there are at least theoretical concerns about administration of Td or Tdap after Menactra.192 Preli-censure data were not available on adverse events after Td or Tdap administered nonsimultaneously after Menactra; postli-censure data are limited but do not suggest that significant adverse events result from sequential administration of diph-theria toxoid–containing vaccines, including Menactra.250 Similarly, a second U.S.-licensed tetravalent meningococcal vaccine, Menveo (Novartis Vaccines and Diagnostics) contains CRM197 as the protein carrier; prelicensure evaluation of this vaccine found a similarly high proportion of vaccinees report-ing injection site pain associated with administration of Tdap, regardless of whether it was given before, simultaneously, or after Menveo.251

Rare Adverse EventsThe potential for anaphylaxis exists with any protein antigen, but has not been attributed to diphtheria toxoid. A recent case series from a food allergy clinic identified eight cases of ana-phylaxis after DTaP or Tdap among children with severe milk allergy; the authors hypothesized that the reaction could have been caused by residual casein.252 This observation has not been replicated in other patient populations. The British National Childhood Encephalopathy Study, designed to examine the incidence of brain damage after the administra-tion of pertussis vaccine, showed a slight but statistically insig-nificant excess of acute encephalopathy in the first 7 days after a dose of DT.253 It is likely, however, that this excess is attribut-able to the induction of inevitable manifestations of preexist-ing central nervous system disorders by the systemic effects of DT, as was observed with infantile spasms.254 Newer studies suggest that many cases of encephalopathy after DTP are among children with severe myoclonic epilepsy of infants (Dravet syndrome), a disorder associated with mutations of the gene encoding the sodium channel.255,256

In 1994, the Institute of Medicine (IOM) reviewed the pos-sible association between tetanus and diphtheria toxoids and Guillain-Barré syndrome (GBS) or polyneuritis. Of 29 reports identified in the medical literature, most cases were in adults who had received tetanus toxoids alone (21 cases) or tetanus toxoid and tetanus antitoxin (four cases). Few cases of GBS or polyneuritis after diphtheria toxoid–containing vaccines have been reported. In 1994, the IOM concluded that the evidence favored a causal relationship between tetanus toxoid and GBS,257 but a more recent report concluded that the evidence was inadequate to either accept or reject a causal relationship

was marked in 2% of subjects; none had erythema or swell-ing noted on examination.239

With current formulations of diphtheria toxoid, the fre-quency of reported adverse events varies by prior vaccination history, prevaccination diphtheria antitoxin level, and dosage of diphtheria toxoid administered. Among 123 persons 30 to 70 years of age with diphtheria antitoxin levels of 0.05 IU/mL or less, adverse events after vaccination were more severe among those who received 12 Lf of diphtheria toxoid without tetanus toxoid as a booster than among those who received dosages of 5 Lf or 2 Lf of diphtheria toxoid without tetanus toxoid, supporting the recommendation to administer reduced dosages of diphtheria toxoid to adults.240 A second study in military recruits 18 to 25 years of age, most of whom had documentation of receipt of a complete primary vaccination series in childhood, also showed no differences in adverse events between dosages of 5 Lf and 2 Lf of diphtheria toxoid when combined with tetanus toxoid.241 A newer study in 180 adults evaluated the reactogenicity of DTaP (9 Lf) with Td (2 IU) and monovalent diphtheria toxoid (2 IU). Although the proportion of vaccinees with local reactions (e.g., ery-thema, induration, warmth, tenderness) was generally lower among recipients of the monovalent diphtheria toxoid than was observed in the other two groups, there was no consistent pattern of increased reactogenicity among recipients of DTaP compared with Td.242

Lower diphtheria toxoid content generally results in decreased reactogenicity of booster doses among children. Among children who had previously received three doses of DTaP containing 25 Lf of diphtheria toxoid at 3, 4, and 5 months of age, booster doses containing varying amounts of antigen and adjuvant were administered as a fourth dose at 15 to 27 months of age. Among 117 children who received vaccine containing a reduced amount of diphtheria toxoid (7.5 Lf) and tetanus toxoid (7.5 Lf compared with 10 Lf), there were significant reductions in the proportion of children with redness (27% vs 50%), swelling (18% vs 39%), or pain (17% vs 30%) compared with the frequency in 859 children who received the 25 Lf-containing preparation. A temperature higher than 38°C was also significantly more common in the group receiving vaccine with higher diphtheria toxoid content (27% compared with 18%). A third group of 117 children received vaccine containing 1.5 Lf of diphtheria toxoid, 10 Lf of tetanus toxoid, and reduced aluminum adjuvant (0.3 mg, compared with 0.5 mg); the proportion of children experienc-ing local reactions was lower than those seen with the 25 Lf vaccine and similar to that seen with 7.5 Lf (28% redness, 25% swelling, 14% pain), but there was no decrease in the proportion with temperature greater than 38°C (28%).243 Diphtheria toxoid content of one-fifth the dosage at 4 to 6 years of age was evaluated in a study of 593 children in Canada, in which the licensed DTaP-IPV combination (Quadracel, Sanofi Pasteur) (15 Lf) was compared with Tdap (Adacel, Sanofi Pasteur) (2 Lf). The proportions of children developing erythema, swelling, pain, and fever were signifi-cantly reduced in the group receiving Tdap with 2 Lf of diph-theria toxoid.244 In the United Kingdom, among children who had previously received meningococcal conjugate vaccine con-taining CRM197, there were similar rates of local reactions and fever among children receiving 30 Lf- and 2 Lf-containing vac-cines at ages 3.5 to 5 years.245

Use of adsorbed vaccine for primary immunization has been reported to result in higher rates of local adverse reactions after subsequent booster vaccination. A higher incidence of local reactions after booster vaccination with DT was observed among Swedish schoolchildren who received adsorbed DT for primary immunization in infancy compared with those who had received nonadsorbed fluid DTP. Seventy-three



1973.5% to 85.9% had protective antibody levels for diphtheria antibodies (>0.01 IU/mL) even when the booster dose was combined or given coadministered with other vaccines such as IPV or hepatitis B (HepB).270–272 For added protection against pertussis, a dose of Tdap is recommended to replace one decennial dose Td in persons who have not received a prior dose of Tdap previously. In some industrialized coun-tries like the United States, United Kingdom, Canada, New Zealand, and Belgium, Tdap is recommended during every pregnancy to protect the newborn against pertussis.273–277 In Latin America, Tdap is recommended for use during preg-nancy situations of high risk such as outbreaks.278

Limited data regarding simultaneous administration of the first three doses of DTaP with other childhood vaccines indicate no interference with response to the diphtheria toxoid compo-nent. Data are available regarding administration of DTaP with other vaccines recommended at the same time as the fourth and fifth doses of the diphtheria, tetanus, and pertussis series (i.e., Hib conjugate vaccine, measles-mumps-rubella vaccine, and varicella vaccine) and regarding administration of whole-cell DTP (all doses in the series) with these vaccines.177,279 DTaP may be administered simultaneously with other routinely recom-mended childhood vaccines, including HepB vaccine, Hib vaccine, inactivated poliovirus vaccine, pneumococcal conju-gate vaccine, and rotavirus vaccine, to infants at ages 2, 4, or 6 months.

As with tetanus toxoid and pertussis vaccine, prolonging the interval between doses does not require restarting the series; indeed, immune responses achieved after longer inter-vals between doses than those recommended are often higher than after the regular schedule, although the subject may be left unprotected in the interim.

In other countries, DTP is administered according to alternative schedules (see Chapters 72 and 74). According to the recommended schedule for the WHO’s EPI, DTP is administered at 6, 10, and 14 weeks. In a number of Euro-pean countries, two doses of DTP or DTaP are administered early in the first year of life, followed by a third dose late in the first year or early in the second year of life. Recommen-dations regarding subsequent boosters vary by country. In response to the epidemic of diphtheria in the former Soviet Union, booster doses have been recommended or reinstated in a number of countries outside the former Soviet Union. WHO now recommends that the primary vac-cination series of three doses starting as early as 6 weeks of age and with a minimum interval of 4 weeks between doses. Where resources are available, additional doses can be given after completion of the primary series. In some countries, additional booster doses are given in the second year of life and a second booster is given at 4 to 7 years of age. WHO recommends that people living in low-endemic or nonen-demic areas should receive a booster dose of diphtheria toxoid approximately 10 years after the primary series and subsequently every 10 years throughout life to sustain immunity, and that particular attention should be given to revaccination of healthcare workers.229

In some countries, booster doses are administered as adult formulations of Tdap to some age groups.

Contraindications and PrecautionsThere are few contraindications to the use of diphtheria toxoid. Severe hypersensitivity reactions after a previous dose are con-sidered contraindications to further doses.268 Even though causation by pertussis vaccine is not established, children who experienced encephalopathy within seven days after adminis-tration of a previous dose of DTaP or Tdap vaccine and not attributable to another cause should not receive additional

between diphtheria toxoid, tetanus toxoid, or acellular pertussis–containing vaccines and GBS.258 Although there is little evidence to support an independent association between receipt of diphtheria toxoid and GBS, cases of GBS have been reported in the United States among recipients of a tetravalent meningococcal conjugate vaccine, in which the meningococ-cal polysaccharides are conjugated to diphtheria toxoid (Men-actra, Sanofi Pasteur).259 A causal relationship between receipt of Menactra and GBS has not been established.

Indications for Vaccine. DTaP is ordinarily not given to infants who are younger than 6 weeks of age because responses to pertussis vaccine in the young infant are suboptimal; responses to tetanus and diphtheria toxoids, however, are sat-isfactory in such young infants regardless of the presence of maternally derived serum antibody and without induction of immunologic tolerance.260 The optimal age for immunization of premature infants cannot be stated with confidence, although available data suggest that satisfactory responses are achieved by initiating the usual DTP series according to the routine immunization schedule regardless of pregnancy duration.261–264 Follow-up of a small group of children born at less than 29 weeks’ gestation suggests lower diphtheria anti-body levels at age 7 years, after a five-dose series, than in children born at term.265 There is evidence that high titers of transplacental antibody to diphtheria toxin inhibit serologic responses to the first two doses of diphtheria toxoid in infants, but after the third dose (administered in the Swedish schedule at 12 months of age), the effect is no longer evident.186

Diphtheria and tetanus toxoids, adsorbed, for pediatric use (DT) is recommended for the primary immunization of chil-dren younger than 7 years in whom pertussis vaccine is con-traindicated. DT contains 10 to 12 Lf of diphtheria toxoid; infants who begin the series before 1 year of age should receive DT at 2, 4, 6, and 15 to 18 months of age. Satisfactory responses are obtained even in the absence of the adjuvant effect of pertussis vaccine.266,267 For unimmunized children 1 to 7 years of age, two doses 2 months apart and a third dose 6 to 12 months later constitute primary immunization.268

Tetanus and diphtheria toxoids, adsorbed, for adult use (Td) contains approximately the same amount of tetanus toxoid as do DTP and DT, but the amount of diphtheria toxoid is reduced to no more than 2 Lf per dose. This reduction minimizes reactivity in persons who may have been sensitized previously to diphtheria toxoid, and it is sufficient to provoke satisfactory anamnestic responses in previously immunized persons.216 In addition, in previously unimmunized older chil-dren and adults, Td is satisfactory for primary immuniza-tion190,269 when administered as a three-dose series, with the second dose given 4 to 8 weeks after the first dose, and the third dose 6 to 12 months after the second dose.262 Td should be administered approximately every 10 years after the com-pletion of childhood immunization, with the first booster dose given as Tdap. Although Td is slightly more reactive than tetanus toxoid alone,235 it is preferable to monovalent tetanus toxoid for prophylaxis of tetanus after wounds to maintain satisfactory population immunity against diphtheria. In the United States, DT and Td are distributed by Sanofi Pasteur, Inc. Monovalent diphtheria toxoid is no longer available in the United States.

Tdap contains a reduced dose of acellular pertussis vaccine and adult formulation diphtheria and tetanus toxoids. Two Tdap vaccines are licensed for use in the United States, with different age indications (see “Preparations Available, Includ-ing Combinations” earlier). Both Tdap products are currently licensed for use as a single booster dose. After 10 years of follow-up from receiving Tdap, 97% to 100% of participants had protective levels of tetanus antibodies (>0.01 IU/mL) and



this epidemic was the proportion of cases occurring among adults, varying from 38% in Azerbaijan to 82% in Latvia and Lithuania in 1994.290 Before 1986, the last dose of diph-theria toxoid was routinely administered at 14 to 16 years of age in the Soviet Union; in response to an increase in reported cases of diphtheria in the early 1980s, targeted vac-cination of certain occupational groups was initiated, but routine use of booster vaccinations among adults was not recommended. Immunogenicity studies in Russia, Ukraine, the Baltic States, and Georgia demonstrated that some adults failed to develop a booster response to a single dose of diphtheria toxoid, suggesting that they may never have received an effective primary series in childhood.225–228,291 Childhood immunization coverage was low in some regions in the late 1980s and early 1990s, in part because of an extensive list of contraindications to vaccination,292 which undoubtedly contributed to the epidemic.293 For control of the epidemic, the WHO recommended identification, isola-tion, and appropriate treatment of all cases; prevention of secondary cases by optimum management of close contacts of cases; and rapidly increasing population immunity by sustaining high coverage among children with four doses of DTP in all districts and administering a single dose of an age-appropriate formulation of diphtheria toxoid to the entire population.290 By 1997, all countries had made signif-icant progress in immunization of children and adults; the declines in disease incidence were most dramatic in coun-tries that had achieved high coverage.64 Diphtheria incidence has continued to decrease. During the period 2000–2009, 7032 cases of diphtheria were reported in the WHO Euro-pean Region, with more than 60% of the cases reported from the Russian Federation. During the decade, diphtheria incidence decreased by more than 95% in the region. By 2009, only Latvia reported an incidence of greater than 1 case per million population.64 During the period 2001–2013, a total of 65,226 cases of diphtheria were reported from the WHO South East Asia Region; approximately 84% were from India.65,140

Disease Control Strategies: United States and OthersThe primary control strategy for prevention of diphtheria globally is routine childhood vaccination with diphtheria toxoid as DTP or DTaP. In countries rendered nonepidemic through high immunization coverage, WHO recommends that the primary vaccination series of three doses be extended by at least one booster dose, and acknowledges that revaccina-tion of adults against diphtheria every 10 years may be neces-sary to sustain immunity.

In the United States, DTaP, is administered as a five-dose series in childhood followed by decennial booster doses of Td beginning at age 11 to 12 years. For added protection against pertussis, Tdap is now recommended for the booster dose at age 11 to 12 years. Td, rather than monovalent tetanus toxoid, should be used in emergency departments, physi-cians’ offices, and other situations in which tetanus-prone wounds are treated.294–296 There are essentially no indications for monovalent tetanus toxoid at present in the United States or elsewhere.

Epidemiological surveillance to ensure the early detection of cases should be in place in all countries, and all countries should have access to laboratory facilities that can provide reliable identification of toxigenic C. diphtheriae. Rapid public health response to a suspected case of diphtheria, with case investigation to identify the source of infection and other persons who may have been exposed, can help limit spread of diphtheria.

doses of a combination vaccine that contains pertussis anti-gens. Local side effects alone do not preclude continued use. Vaccination of persons with severe, febrile illness generally should be deferred until recovery, but mild illnesses with or without fever should not preclude vaccination.

Some diphtheria toxoid products are packaged in contain-ers (vials or syringes) containing latex rubber. If a person reports a severe anaphylactic allergy to latex, vaccines supplied in vials or syringes that contain natural rubber should not be administered, unless the benefit of vaccination outweighs the risk of an allergic reaction to the vaccine. For latex allergies other than anaphylactic allergies (e.g., a history of contact allergy to latex gloves), vaccines supplied in vials or syringes that contain natural rubber or natural rubber latex can be administered.280

Persons with a bleeding disorder or receiving anticoagulant therapy may receive indicated vaccinations by the intramuscu-lar route if, in the opinion of a physician familiar with the patient’s bleeding risk, the vaccine can be administered with reasonable safety by this route. A fine needle (23 gauge or smaller) should be used for the injection and firm pressure applied to the site, without rubbing, for 2 or more minutes. The patient or family should be instructed concerning the risk for hematoma from the injection.281

PUBLIC HEALTH CONSIDERATIONSEpidemiologic Effects of VaccinationDespite the relatively low levels of immunity among adults in many countries, diphtheria has remained well controlled in most countries with effective childhood immunization pro-grams. Historically, it has been thought that 70% or more of a childhood population must be immune to diphtheria to prevent major community outbreaks281; the herd immunity threshold has been estimated to be 80% to 85%, based on the average age of infection in the prevaccine era.282 Whether an epidemic of a given infectious disease occurs is influenced by a number of factors other than the proportion of susceptible persons in the population, including the age distribution of immune and susceptible persons, the extent of mixing of indi-viduals and subgroups in the community, and the infectivity and routes of transmission of the organism.215 In countries with high rates of childhood immunization against diphthe-ria, it may well be that epidemics do not occur among adults, up to half of whom may be susceptible, because the reservoir of disease in the childhood population has been eliminated and because the strains of C. diphtheriae circulating in the community are less likely to be toxigenic.

Serologic studies in Europe and the United States demon-strate that many adults in these countries remain susceptible to diphtheria.223,283–289 Differences in seroprevalence among countries reflect the varied immunization schedules and vac-cination coverage among countries, the effect of immuniza-tion during military service, and the unknown effects of natural exposure to toxigenic C. diphtheriae.141,142,223 Although there is some variability among countries, studies of diphthe-ria seroprevalence frequently have demonstrated low levels of immunity among older adults. In 1996, a serologic study in England and Wales showed that only 29% of adults age 60 years and older had diphtheria antitoxin titers of 0.01 IU/mL or greater.290 A similar pattern of susceptibility is seen among elderly persons in other countries of Western Europe.223 Some studies also demonstrated less susceptibility among males; in some countries, this may reflect immunization during military service.223

These concerns have been heightened by the epidemic of diphtheria in the former Soviet Union. A striking feature of



19diphtheria toxin,299 and an animal reservoir does exist for this organism300,301 and thus for the bacteriophage. Given the worldwide ubiquity of carriage of C. diphtheriae and the bac-teriophages implicated in toxin production, prospects for eradication of diphtheria currently seem remote. Continuing active immunization with diphtheria toxoid is the key to the control of diphtheria.

FUTURE VACCINESNew combination vaccines for use in young children built on both the DTaP and DTP backbone are under development.302 Alternative approaches to diphtheria immunization in the future may include vaccination by the oral303,304 or nasal305 routes or use of a highly purified, less-reactive antigen306–308 or carrier systems309,310 for diphtheria toxoid that would require fewer injections. Such products would be particularly useful in the developing world, where severe limitations in health-care personnel and financial resources are major barriers.

References for this chapter are available at ExpertConsult.com.

Cost-to-Benefit InformationThe costs and benefits of diphtheria toxoid as a component of DTP or DTaP, administered as part of the routine immuni-zation series have been evaluated on several occasions. In 1997, it was estimated that diphtheria vaccination prevented almost all the 276,750 diphtheria cases and 27,675 diphtheria deaths that were estimated to occur in the absence of vaccina-tion among a simulated birth cohort of 4.1 million children during the first 15 years of life; both were cost-saving from the societal and healthcare system perspectives.297 A similar analy-sis evaluated DTaP as part of the 2001 recommended child-hood immunization schedule, which also included Hib vaccine, IPV, measles-mumps-rubella vaccine, HepB vaccine, and varicella vaccine. Vaccination of a hypothetical U.S. birth cohort was estimated to result in savings of more than $2 billion in direct costs and $24 billion in total costs for cases of diphtheria prevented and was cost saving both in terms of direct costs (benefit-to-cost ratio: 5.3) and from the societal perspective (benefit-to-cost ratio: 16.5).298

ERADICATIONAlthough no animal reservoir exists for C. diphtheriae, C. ulcerans may carry the β-corynebacteriophage that encodes


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Diphtheria Toxoid 275.e1

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http://www.bpac.org.nz/BPJ/2013/March/docs/BPJ51-pages-34-38.pdf

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