Diphtheria

Approximately 0.001 cases per 100,000 population in USA since 1980 (<5 cases a year).

Endemic in developing countries.

Still common in countries where mass immunization programs are not enforced.

After political changes in Eastern Europe and Central Asia at the end of the 20th century, a resurgence in many vaccine-preventable diseases, including diphtheria, was reported across these countries.

Risk factors for diphtheria outbreaks: older age (they are not up to date with booster immunization against diphtheria), lack of vaccination, alcoholism, low socioeconomic status, crowded living conditions, and Native American background.

Early (days after exposure): Respiratory compromise; respiratory arrest; airway obstruction and hemorrhage; conduction abnormalities, dysrhythmia, cardiogenic shock, CHF, myocarditis; shock, coma, and death

Late (2–6 wk): Myocarditis and polyneuritis

Respiratory diphtheria early toxic manifestations: neck edema, pharyngitis, large pseudomembranes, massive swelling of the tonsils, bull-neck diphtheria (with massive edema of the submandibular and paratracheal region and foul breath, thick speech, and stridor), hoarseness, and difficulty breathing are associated with severe advanced disease/poor prognosis and with a significant early risk of total airway obstruction.

Late toxic manifestations of diphtheria: polyneuropathy (resembles Guillain-Barré syndrome) and myocarditis (cardiac arrhythmias, conduction abnormalities, or CHF).

Other complications: Septic arthritis, pneumonia, renal failure, endocarditis, encephalitis, cerebral infarction, and pulmonary embolism.

Fatal pseudomembranous diphtheria typically occurs in pts with nonprotective antibody titers and in unimmunized pts. Death occurs in 5–10% of respiratory cases. Risk factors for death include bull-neck diphtheria, myocarditis with ventricular tachycardia, atrial fibrillation or complete heart block, an age of >60 y or <6 mo, alcoholism, extensive pseudomembrane elongation, and laryngeal, tracheal, or bronchial involvement, and delayed antitoxin administration.

Diphtheria is caused by superficial infection of the respiratory tract or skin with toxin-producing strains of Corynebacterium diphtheriae. The pathogens multiply locally and produce diphtheria toxin. This results in necrosis of the mucosal cells and production of a thick, gray pseudomembrane containing fibrin, epithelial cells, bacteria, and neutrophils. Diffusion of toxin in the circulation causes toxic neurologic and myocardial complications.

The major risk factor for C. diphtheriae infection continues to be travel to an endemic country (Indian subcontinent, Africa, or South East Asia).

Prompt consideration of diphtheria: Severe pharyngitis, difficulty swallowing, respiratory compromise, or signs of systemic disease, including myocarditis or generalized weakness, and presence of a pharyngeal pseudomembrane or an extensive exudate.

Respiratory diphtheria: Sore throat with low-grade fever and a strongly adherent pseudomembrane of the tonsils, pharynx, or nose. Occasionally weakness, dysphagia, headache, and voice change. The diphtheritic pseudomembrane is gray or whitish, sharply demarcated and tightly adherent to the underlying tissues. Respiratory diphtheria can progress to a swollen so-called bull neck, and the pseudomembrane can progress to cause airway obstruction. Attempts to dislodge the membrane may cause bleeding. Respiratory diphtheria remains the most common clinical presentation.

Systemic toxin-mediated neurologic and cardiac toxicity of diphtheria: Neuritis and polyneuropathy (cranial nerve involvement, respiratory and abdominal muscle weakness, generalized sensorimotor polyneuropathy and autonomic manifestations), and myocarditis (dysrhythmia of the conduction tract, dilated cardiomyopathy, congestive failure and circulatory collapse).

Cutaneous diphtheria: Painful infected skin lesions and nonhealing or enlarging skin ulcers which lack a characteristic appearance. Cutaneous diphtheria has a low mortality rate, rarely associated with myocarditis or peripheral neuropathy.

Invasive disease: Bacteremia, endocarditis, mycotic aneurysms, osteomyelitis, and septic arthritis.

Corynebacteria are Gram-positive rods (nonsporulating, nonencapsulated, and nonmotile Gram-positive bacillus). Many species from this genus are skin commensals and act only as opportunistic pathogens. Of the many Corynebacterium species, three can potentially produce a diphtheria toxin and cause diphtheria or diphtheria-like diseases: C. diphtheriae, C. ulcerans , and C. pseudotuberculosis.

Historically the most commonly identified causative bacterium is C. diphtheriae. Human beings are the reservoir for C. diphtheriae , in particular children, and transmission of C. diphtheriae occurs from person to person, predominantly from the respiratory tract (via the aerosol route) but occasionally from cutaneous lesions or fomites. The incubation period for respiratory diphtheria is usually 2–5 d but occasionally is longer, with duration of up to 10 d reported.

Two human isolate phenotypes: Nontoxigenic and toxigenic. C. diphtheriae, C. ulcerans , and C. pseudotuberculosis toxigenic strains express diphtheria exotoxin (mechanism of pathogenesis during human infection) that inhibits protein synthesis and kills susceptible cells. Toxin is produced in the pseudomembranous lesion and distributed to all organ systems through the blood. Toxigenic strains cause pharyngeal/respiratory and cutaneous diphtheria, and systemic diseases. The clinical and epidemiologic significance of nontoxigenic strains remains unclear. Nevertheless, cases caused by nontoxigenic strains have been reported in immunocompromised individuals.

Laboratory diagnosis is by culture of an isolate of Corynebacterium species. qPCR assay identifies Corynebacterium species, plus the presence of the tox gene (diphtheria exotoxin) in DNA extracts from submitted isolates. If the tox gene is detected, the isolate goes to have an Elek test to detect expression of toxin.

C. ulcerans is now more frequently reported and can also cause the same ranges of diphtheria-like illness. By contrast, the C. ulcerans reservoir is thought to be animals. It has been reported after consumption of raw dairy products and contact with cattle, pigs, and domestic pets. C. ulcerans diphtheria person-to-person transmission is proposed, but is not confirmed. C. pseudotuberculosis is also traditionally associated with farm animal contact and dairy products.