90 Diphtheria 931

CHAPTER 90 Diphtheria 931 SUBSECTION III Gram-Positive Bacilli Diphtheria 90 Barbara W. Stechenberg Diphtheria is an acute infectious disease caused by Corynebacterium in mortality rates by a therapeutic intervention. In Germany alone, an diphtheriae or, less commonly, C. ulcerans. C. pseudotuberculosis, which estimated 45,000 lives were saved each year.62 primarily causes infections in sheep and goats, is not discussed here because it only rarely causes a diphtheria-like disease in humans. Infection by toxigenic strains of C. diphtheriae causes disease that is mediated by ETIOLOGY the production of an extracellular protein. Nontoxigenic strains also Corynebacteria (Klebs-Löffler bacilli) are irregularly staining, gram- can cause disease, but it is usually less severe. positive, nonmotile, nonsporulating, pleomorphic bacilli.54 The club- Before the discovery of antitoxin at the turn of the 20th century, shaped appearance of the bacillus is not a true morphologic feature, the “strangling angel of children,” as diphtheria once was called, was a but results from attempting to grow the bacillus on media that are significant cause of mortality in children and adults.108 Apparent reference nutritionally inadequate (Löffler media). The organism can be recovered to diphtheria can be traced to the 5th century BC in the works of Hip- most readily on media containing selective inhibitors that retard the pocrates, Epidemics III, case 7.79 In 1821, it was recognized as a specific growth of other microorganisms; a sheep blood agar–based medium entity by Brettoneau, who suggested that the disease was caused by a containing fosfomycin (for selectivity) and Tindale medium (tellurite germ and that it could be transmitted from person to person. Brettoneau medium with cystine) are ideal.43,44 C. diphtheriae and C. ulcerans coined the origin of the modern term diphtheria from the Greek root grow on supplement-free blood agar, chocolate agar, and other standard diphtheria, which means “skin” or “hide.”50 In 1883 the causative agent media.43 was identified by Klebs in stained smears from diphtheritic membranes; Colonies of C. diphtheriae (with the exception of the lipophilic, gray in 1884, Löffler grew the organism on artificial media and showed that C. intermedius) and C. ulcerans appear grayish white on Löffler medium. in guinea pigs it caused a fatal infection closely resembling human On tellurite medium, three diphtheria colony types can be distinguished: disease. mitis, gravis, and intermedius. Mitis colonies are smooth, black, and The toxin was purified in 1889 by Roux and Yersin, who found that convex; they do not ferment starch or glycogen and are hemolytic. toxin alone could cause the disease. Shortly thereafter, Behring and Gravis colonies are gray, radially striate, and semirough; they ferment Kitasato discovered antitoxins when they immunized animals with toxins starch and glycogen and usually are not hemolytic. Intermedius colonies rather than bacteria. The use of antitoxin to treat children with diphtheria are small and smooth and have a black center; they do not ferment at the turn of the 20th century resulted in one of the largest decreases starch or glycogen and are not hemolytic. C. ulcerans colonies resemble 932 SECTION 16 Bacterial Infections gravis on Tindale medium but differ in that they are hemolytic. Similar Diphtheria toxin is lethal to humans in an amount of approximately to gravis, they ferment starch and glycogen. All diphtheria biotypes and 130 µg/kg body weight. Cytoplasmic internalization of 1 molecule of C. ulcerans are characterized by cystinase activity and absence of pyra- toxin has been shown to cause cell death.11 Toxigenic and nontoxigenic zinamidase activity. C. ulcerans may be distinguished from C. diphtheriae strains of C. diphtheriae can cause disease, but only strains that produce by its urease activity and ability to liquefy gelatin. Biotype belfanti, toxin cause disease with symptoms of myocarditis and neuritis. which does not occur in a toxigenic form, may be distinguished from the three potentially toxigenic diphtheria biotypes by its inability to reduce nitrate on Tindale medium and from C. ulcerans by its lack of EPIDEMIOLOGY production of urease.43 Ribotyping and pulsed-field gel electrophoresis, Asymptomatic human carriers serve as the reservoir for C. diphtheriae. both of which involve restriction digestion of genomic bacterial DNA, Infection by C. diphtheriae is acquired by contact with either a carrier followed by gel electrophoresis and Southern blotting, permit more or an individual with active disease. The bacteria may be transmitted specific typing within each diphtheria biotype and aid in the epide- via droplets during coughing, sneezing, or talking. Rarely transmission miologic study of outbreaks.41,95 of C. diphtheriae occurs from skin lesions or fomites. Some reports C. diphtheriae biotypes intermedius, gravis, and mitis and C. ulcerans suggest that skin carriers of C. diphtheriae are more infectious than all have been observed in a toxigenic form. Intermedius was the biotype nose or throat carriers and that skin carriers may serve as potential isolated most commonly in the United States between 1971 and 1981. reservoirs for the initiation of epidemic spread.12,68 In areas in which Of the strains isolated, intermedius was found to be toxigenic more skin infections are endemic, levels of natural immunization may be often than mitis or gravis.36 In the United Kingdom between 1993 and high.20 This phenomenon is illustrated particularly well in a survey of 1998, and similarly in other parts of Europe, the biovar gravis has tetanus and diphtheria immunity in a rural Kenyan community, where represented most nontoxigenic isolates, followed by mitis and belfanti.45 age was not found to be predictive of immunity, and no correlation Of the four nontoxigenic isolates obtained during a surveillance study was found between levels of antibody for tetanus and diphtheria.77 of a U.S. Northern Plains Native American Community in 1996, two Person-to-person transmission of C. ulcerans is not known to occur, were of biotype mitis and two were gravis.59 According to a UK diphtheria although C. ulcerans was isolated from the siblings of two patients reference laboratory, between 1993 and 1998, the toxigenic isolates reported in the United Kingdom between 1995 and 1997.17 Cases of originating from Asia, Africa, and the Middle East were reported to be respiratory diphtheria caused by C. diphtheriae and C. ulcerans have of the biotype mitis or gravis, with the exception of one intermedius been documented in association with contaminated unpasteurized milk isolate.44 Golaz and associates59 reported similar findings when they taken from cows with infected teats.18,60,104 C. diphtheriae has been isolated surveyed the different biotypes in South Dakota. A significant overall from horses, dogs, and other domestic animals. C. ulcerans has been increase in the proportion of nontoxigenic isolates has been observed reported to infect ground squirrels in the United States, but transmission in Europe and Australia in recent years.58 The reason for this increase to humans has not been reported.67,93 C. ulcerans is a commensal in is unclear, but one hypothesis is that increased immunity to toxigenic animals and has been isolated in a wide range of wild and domestic strains secondary to immunization has altered this epidemiology. animals.105 The complete genome sequence of C. diphtheriae biotype gravis has According to World Health Organization (WHO) reports, diphtheria been elucidated.33 The genome is approximately 2.48 Mb with a G+C is distributed worldwide and remains endemic in many developing areas content of 53% and has approximately 2320 predicted coding sequences. of the world, including Asia, Africa, South America, and the Mediterranean Metabolic analysis of the genome has revealed that C. diphtheriae has regions.19 Worldwide, diphtheria epidemics have occurred in a cyclic a complete set of enzymes for glycolysis, gluconeogenesis, pentose- manner since the 16th century. In 2014, 7321 cases of diphtheria were phosphate pathways, anaerobic and aerobic respiration, amino acid reported to the WHO, although many others were likely unreported. biosynthesis, and purine nucleotide biosynthetic pathway. Most of the In the United States, the incidence and mortality rates from diphtheria enzymes for the tricarboxylic acid cycle are present, with the exception in the 1920s were 140 to 150 cases/100,000, with 13,000 to 15,000 deaths of an enzyme succinyl coenzyme A (CoA) synthetase that catalyzes the each year. The number of cases gradually declined to 15 cases/100,000 conversion of succinate to succinyl CoA. An alternative enzyme present population in 1945 with the extensive use of diphtheria toxoid vaccine. in C. diphtheriae may fulfill this conversion, however. The pyrimidine From 1970 through 1979, the average number of cases of diphtheria pathway in C. diphtheriae lacks an enzyme that interferes with the reported annually in the United States was 196.8 From 1980 to 2004, production of cytidine; the pathway to the biosynthesis of thymidine only 57 cases of diphtheria were reported in the United States. Approxi- is complete. The genome has revealed 13 regions that are unique to C. mately 75% of the cases were in patients older than 15 years who were diphtheriae and may serve as pathogenicity islands.33 unimmunized or inadequately immunized.8 Only two cases of diphtheria No functional or significant differences have been

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