Diphtheria is a nasopharyngeal and skin infection caused by Corynebacterium diphtheriae. Toxigenic strains of C. diphtheriae produce a protein toxin that causes systemic toxicity, myocarditis, and polyneuropathy. The toxin is associated with the formation of pseudomembranes in the pharynx during respiratory diphtheria. While toxigenic strains most frequently cause pharyngeal diphtheria, nontoxigenic strains commonly cause cutaneous disease.
In the United States and Europe, diphtheria has been controlled in recent years with effective vaccination, although sporadic outbreaks have occurred. Diphtheria is still common in the Caribbean, Latin America, and the Indian subcontinent, where mass immunization programs are not enforced. Large epidemics have occurred in the independent states formerly encompassed by the Soviet Union. Additional outbreaks have been reported in Algeria, China, and Ecuador.
C. diphtheriae is a gram-positive, unencapsulated, nonmotile, nonsporulating bacillus. C. diphtheriae organisms have a characteristic club-shaped bacillary appearance and typically form clusters of parallel rays (palisades) that are referred to as Chinese characters. In the specific laboratory media recommended for the cultivation of C. diphtheriae, tellurite, colistin, or nalidixic acid allows selective isolation of the organism in the presence of other autochthonous pharyngeal microbes. Human isolates of C. diphtheriae may display nontoxigenic (tox−) or toxigenic (tox+) phenotypes. Corynebacteriophage beta carries the structural gene (tox) encoding diphtheria toxin, and a family of closely related corynebacteriophages are responsible for toxigenic conversion of tox−C. diphtheriae to the tox+ phenotype. Moreover, lysogenic conversion from a nontoxigenic to a toxigenic phenotype has been shown to occur in situ. Growth of toxigenic strains of C. diphtheriae under iron-limiting conditions leads to the optimal expression of diphtheria toxin, and these conditions are believed to trigger tox expression and subsequent pathogenesis during human infection.
C. diphtheriae is transmitted via the aerosol route, primarily during close contact. There are no significant reservoirs other than humans. The incubation period for respiratory diphtheria is 2–5 days; however, disease can develop as long as 10 days after exposure. Before the vaccine era, most individuals over the age of 10 were immune to C. diphtheriae; infants were protected by maternal IgG antibodies but became susceptible after ∼6 months of age. Thus, the disease was seen primarily in children and nonimmune young adults. In temperate regions, respiratory diphtheria occurs year-round but is most common during winter months.
The development of diphtheria antitoxin and diphtheria toxoid vaccine led to the near-elimination of diphtheria in Western countries. The annual peak incidence rate was 191 cases per 100,000 population in the United States in 1921; in contrast, since 1980, the annual figure for the United States as a whole has been <5 cases. Nevertheless, pockets of colonization have persisted in North America, particularly in South Dakota, Ontario, and Washington state. Immunity induced by vaccination during childhood gradually decreases in adulthood. An estimated 30% of men 60–69 years old have antitoxin titers below the protective level. In addition to older age and lack of vaccination, risk factors for diphtheria outbreaks include alcoholism, low socioeconomic status, crowded living conditions, and Native American ethnic background. An outbreak that occurred in Seattle in 1972–1982 included 1100 cases, primarily manifesting as cutaneous disease. During the 1990s in the states of the former Soviet Union, a much larger diphtheria epidemic caused >150,000 cases and >5000 deaths. Clonally related toxigenic C. diphtheriae strains of the ET8 complex were associated with this outbreak. Given that the ET8 complex expressed a toxin against which the prevalent diphtheria toxoid vaccine was effective, the epidemic was attributed to failure of the public health infrastructure to effectively vaccinate the population. Beginning in 1998, the epidemic was controlled by mass vaccination programs. During the epidemic, the incidence rate was high among individuals from >15 years of age up to 50 years of age. Socioeconomic instability, migration, deteriorating public health programs, frequent vaccine shortages, delays in implementation of vaccination and of treatment in response to cases, and lack of public education and awareness were contributing factors in that outbreak.
Significant outbreaks of diphtheria and diphtheria-related mortality continue to be reported from many developing countries, particularly in Africa and Asia. Statistics collected by the World Health Organization indicate the occurrence of ∼7000 reported diphtheria cases in 2008 and ∼5000 diphtheria deaths in 2004. Although ∼82% of the global population has been adequately vaccinated, only 26% of countries have successfully vaccinated >80% of individuals in all districts.
Cutaneous diphtheria is usually a secondary infection that follows a primary skin lesion due to trauma, allergy, or autoimmunity. Most often, isolates from cases of cutaneous disease lack the tox gene and therefore do not express diphtheria toxin. In tropical regions, cutaneous diphtheria is more common than respiratory diphtheria. In contrast to respiratory disease, cutaneous diphtheria is not a reportable disease in United States.
Nontoxigenic strains of C. diphtheriae have also been associated with bacteremia and invasive disease in the urban poor in Vancouver, Canada, and with pharyngitis in Europe. Outbreaks have occurred among homosexual men and IV drug users.
Pathogenesis and Immunology
Diphtheria toxin, produced by toxigenic strains of C. diphtheriae, is the primary virulence factor in clinical disease. The toxin is synthesized in precursor form; is released as a 535-amino-acid, single-chain protein; and has an LD50 of ∼100 ng/kg of body weight. The toxin is produced in the pseudomembranous lesion and is taken up into the bloodstream, through which it is distributed to all organ systems. Once bound to its cell surface receptor (a heparin-binding, epidermal growth factor–like precursor), the toxin is internalized by receptor-mediated endocytosis and enters the cytosol from an acidified early endosomal compartment. In vitro, the toxin may be separated into two chains after digestion with serine proteases: the N-terminal A fragment and the C-terminal B fragment. Delivery of the A fragment into the eukaryotic cell cytosol results in irreversible inhibition of protein synthesis by NAD+-dependent ADP ribosylation ...