Chapter 131. Diphtheria and Other Infections Caused by Corynebacteria and Related Species (Part 2)

Pathogenesis and ImmunologyDiphtheria 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 receptormediated endocytosis and enters the cytosol from an acidified early endosomal compartment. ...
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Chapter 131. Diphtheria and Other Infections Caused by Corynebacteria and Related Species (Part 2) Chapter 131. Diphtheria and Other Infections Caused by Corynebacteria and Related Species (Part 2) Pathogenesis and Immunology Diphtheria toxin, produced by toxigenic strains of C. diphtheriae, is theprimary virulence factor in clinical disease. The toxin is synthesized in precursorform; 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 pseudomembranouslesion and is taken up into the bloodstream, through which it is distributed to allorgan 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 endosomalcompartment. In vitro, the toxin may be separated into two chains after digestionwith 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 irreversibleinhibition of protein synthesis by NAD+-dependent ADP ribosylation ofelongation factor 2. The eventual result is the death of the cell. In 1926, Ramon at the Institut Pasteur found that formalinization ofdiphtheria toxin resulted in the production of diphtheria toxoid, which wasnontoxic but highly immunogenic. Subsequent studies showed that immunizationwith diphtheria toxoid elicited antibodies that neutralized the toxin and preventedmost manifestations of diphtheria. In the 1930s, mass immunization of childrenand susceptible adults commenced in the United States and Europe. Individuals with an antitoxin titer of >0.01 unit/mL are at low risk ofdiphtheria disease. In populations where a majority of individuals have protectiveantitoxin titers, the carrier rate for toxigenic strains of C. diphtheriae decreasesand the overall risk of diphtheria among susceptible individuals is reduced.Nevertheless, individuals with nonprotective titers may contract diphtheriathrough either travel or exposure to individuals who have recently returned fromregions where the disease is endemic. Characteristic pathologic findings of diphtheria include mucosal ulcers witha pseudomembranous coating composed of an inner band of fibrin and a luminalband of neutrophils. Initially white and firmly adherent, in advanced diphtheria thepseudomembranes turn gray and even green or black as necrosis progresses.Mucosal ulcers result from toxin-induced necrosis of the epithelium accompaniedby edema, hyperemia, and vascular congestion of the submucosal base. Afibrinosuppurative exudate from the ulcer develops into the pseudomembrane.Ulcers and pseudomembranes in severe respiratory diphtheria may extend fromthe pharynx into medium-sized bronchial airways. Expanding and sloughingmembranes may result in fatal airway obstruction. Approach to the Patient: Diphtheria Although diphtheria is rare in the United States and other developedcountries, this diagnosis should be considered in patients who have severepharyngitis, particularly with difficulty swallowing, respiratory compromise, orsigns of systemic disease including myocarditis or generalized weakness. In thedifferential diagnosis, the leading causes of pharyngitis that should be consideredare respiratory viruses (rhinoviruses, influenza viruses, parainfluenza viruses,coronaviruses, and adenoviruses; ~25% of cases), group A streptococci (15–30%),group C streptococci (~5%), atypical bacteria such as Mycoplasma pneumoniaeand Chlamydophila pneumoniae (15–20% in some series), and other viruses suchas herpes simplex virus (~4%) and Epstein-Barr virus (EBV; Respiratory diphtheria due to toxigenic C. diphtheriae producingexudative pharyngitis in a 47-year-old woman with neck edema and apseudomembrane extending from the uvula to the pharyngeal wall. Thecharacteristic white pseudomembrane is caused by diphtheria toxin–mediatednecrosis of the respiratory epithelial layer, producing fibrinous coagulativeexudate. Submucosal edema adds to airway narrowing. The pharyngitis is acute inonset, and respiratory obstruction from the pseudomembrane may occur in severecases. Inoculation of pseudomembrane fragments or submembranous swabs ontoLöfflers or tellurite selective medium reveals C. diphtheriae. (Photograph by P.Strebel, MD, used by permission. From Kadirova et al.)