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INTRODUCTION

At the beginning of the twentieth century, respiratory diphtheria was a major cause of childhood disease and death worldwide, but widespread use of safe and efficacious diphtheria toxoid-containing vaccines (DTCV) in industrialized nations starting in the 1940s reduced disease incidence significantly by the 1980s. However, diphtheria re-emerged as a public health threat in the 1990s, when a massive diphtheria epidemic occurred in the newly independent states of the former Soviet Union, with over 157,000 cases and 5000 deaths reported.1 Since 2010, multiple large diphtheria outbreaks been reported globally, including in Indonesia,2 Laos,3 Thailand,4 Haiti,5 Venezuela,5 South Africa,6 India,7 Bangladesh,8 and Yemen.9 Recent outbreaks illustrate the potential for this vaccine-preventable disease to spread following decades of successful control, particularly in countries with economic decline and civil unrest, population displacement, and collapse of public health infrastructure accompanied by decreased delivery of childhood vaccination programs. In addition to causing outbreaks, diphtheria is endemic in under- and un-vaccinated populations and in countries where childhood DTCV coverage is persistently below 80%.10,11 Maintaining high levels of vaccination in both children and adults is critical to provide both individual protection and population immunity.

ETIOLOGICAL AGENT, TRANSMISSION, PATHOGENESIS, AND DIAGNOSIS

Diphtheria is a potentially life-threatening disease caused by toxin-producing strains of Corynebacterium diphtheriae. The organism is a gram-positive, nonmotile, nonencapsulated, nonsporulating rod-shaped bacillus that was first described as the etiologic agent of diphtheria in 1884. Some C. diphtheria strains can produce diphtheria toxin, a very potent exotoxin; strains becomes toxigenic when lysogenized by beta-(β) corynebacteriophages that harbor tox, the structural gene for diphtheria toxin.12 There are four biotypes of C. diphtheria: gravis, mitis, intermedius, and belfanti. All C. diphtheria biotypes can become toxigenic and cause disease with similar pathogenicity and severity. In addition, two other zoonotic Corynebacterium species, C. ulcerans and C. pseudotuberculosis, can be lysogenized by β-corynebacteriophages and cause toxin-mediated illness in humans with a similar clinical presentation to that of toxigenic C. diphtheriae.13,14 Although possible, person-to-person transmission of these two zoonotic species has not been established.14,15

The reservoir for C. diphtheriae is humans, although toxigenic organisms have been occasionally recovered from other animals, including infected horses and dogs.16-18 Transmission of C. diphtheriae generally occurs by droplet spread from respiratory sites of either infected persons or carriers. Transmission can also occur through direct contact with discharge from infected skin lesions. Environmental contamination with C. diphtheriae has been documented; however, transmission via contaminated fomites is presumed to be rare.19,20

The most common anatomic sites for infection are the mucosal lining of the respiratory tract (i.e., nares, nasopharynx, tonsils, or larynx), and the skin. Rarely, other mucosal sites, such as the conjunctiva, ear, and genitalia are affected. In susceptible persons, diphtheria toxin binds to a wide range of cells, blocks protein synthesis, and causes cell ...

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