Introduction

Diphtheria is an infectious disease of humans that affects the respiratory tract or skin. It is caused by toxigenic (toxin-producing; tox+) isolates of Corynebacterium diphtheriae or, rarely, Corynebacterium ulcerans.[1,2] A pseudomembrane at the site of infection occurs commonly in respiratory diphtheria and occasionally in cutaneous diphtheria. The major bacterial virulence factor involved in pathogenesis is diphtheria toxin, which blocks protein synthesis and has a lethal dose of <0.1 mg/kg of body weight.[3,4] Diphtheria toxin is encoded by certain coryne-bacteriophages, and all toxigenic variants of C. diphtheriae or C. ulcerans are lysogenic for a tox+ prophage. Toxin produced locally can spread via the bloodstream and damage vital organs, including the heart, peripheral nerves, kidneys, liver, and adrenal glands.[5] Both toxi-genic and nontoxigenic variants of C. diphtheriae can cause infections of mucous membranes or skin, but only tox+ strains are associated with the harmful manifestations caused by diphtheria toxin. Definitive diagnosis of diphtheria is based on clinical findings compatible with diphtheria plus isolation of C. diphtheriae or demonstration of characteristic histopathological findings. Respiratory diphtheria, but not cutaneous diphtheria, is reportable in the United States.

Diphtheria has been nearly eliminated in developed countries by widespread immunization with diphtheria toxoid, an immunogenic but nontoxic derivative of diphtheria toxin.[6] Antibodies raised against diphtheria toxoid by active immunization combine with diphtheria toxin and neutralize its toxic effects. When a clinical diagnosis of diphtheria is made, equine diphtheria antitoxin is administered immediately to the patient as a therapeutic measure without waiting for bacteriological cultures, because delays in administration of antitoxin are associated with greater mortality.[2] Immunization with diphtheria toxoid prevents diphtheria, but it does not eliminate carriage of tox+ C. diphtheriae in the human population.[7] Diphtheria has the potential to reemerge if immunity is not maintained at a high level in the population. The most devastating recent outbreak of reemergent diphtheria occurred in Russia and the Newly

Independent States (NIS) of the former Soviet Union during the early and mid-1990s, resulting in >150,000 cases and >5000 deaths.[8,9] At least 20 imported cases of diphtheria in adults were diagnosed in Central and Western European countries following exposures that occurred in the epidemic regions.

When C. diphtheriae is isolated from a clinical specimen, the most critical issue is to determine rapidly and accurately whether the isolate is tox+. This is important to assure that individual patients receive proper treatment, determine if contacts require prophylactic treatment, and assess whether immunization programs or other measures are required to prevent the spread of diphtheria within the population at risk. Toxigenicity testing (originally called virulence testing) on isolates of C. diphtheriae can be performed either directly by using bioassays that detect specific toxic effects of diphtheria toxin or indirectly by using molecular methods that detect antigenic determinants of the diphtheria toxin protein or specific nucleotide sequences within the structural gene for diphtheria toxin (tox). This chapter summarizes the current status of phenotypic and genotypic tests for diphtheria toxin, with emphasis on test formats that have been used recently by several major diphtheria reference laboratories.

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