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Diphtheria is an acute toxic infection caused by Corynebacterium species, typically Corynebacterium diphtheriae and, less often, toxigenic strains of Corynebacterium ulcerans. Although diphtheria was reduced from a major cause of childhood death to a medical rarity in the Western hemisphere in the early 20th century, recurring reminders of the fragility of this success, particularly in conflict areas, emphasize the need to continue vigorous promotion of those same control principles across the global community.
Corynebacteria are aerobic, nonencapsulated, non–spore-forming, mostly nonmotile, pleomorphic, gram-positive bacilli. C. diphtheriae is by far the most frequently isolated agent of diphtheria. C. ulcerans is more often isolated from animal sources and can cause human disease similar to C. diphtheriae . Selective medium (e.g., cystine-tellurite blood agar or Tinsdale agar) that inhibits growth of competing organisms is required for isolation and, when reduced by C. diphtheriae, renders colonies gray-black. Differentiation of C. diphtheriae from C. ulcerans is based on urease activity; C. ulcerans is urease-positive. Four C. diphtheriae biotypes ( mitis, intermedius, belfanti, gravis ) are capable of causing diphtheria and are differentiated by colony morphology, hemolysis, and fermentation reactions. The ability to produce diphtheritic toxin results from acquisition of a lysogenic corynebacteriophage by either C. diphtheriae or C. ulcerans, which encodes the diphtheritic toxin gene and confers diphtheria-producing potential on these strains. Thus, indigenous nontoxigenic C. diphtheriae can be rendered toxigenic and disease-producing after importation of a toxigenic C. diphtheriae . Demonstration of diphtheritic toxin production by the modified Elek test, an agar immunoprecipitin technique, alone or in conjunction with polymerase chain reaction (PCR) testing for carriage of the toxin gene, is necessary to confirm disease. Toxigenic and nontoxigenic strains are indistinguishable by colony type, microscopic features, or biochemical test results.
Unlike other diphtheroids (coryneform bacteria), which are ubiquitous in nature, C. diphtheriae is an exclusive inhabitant of human mucous membranes and skin. Spread is primarily by airborne respiratory droplets, direct contact with respiratory secretions of symptomatic individuals, or exudate from infected skin lesions. Asymptomatic respiratory tract carriage is important in transmission. In areas where diphtheria is endemic, 3–5% of healthy individuals can carry toxigenic organisms, but carriage is exceedingly rare when diphtheria is rare. Skin infection and skin carriage are silent reservoirs of C. diphtheriae, and organisms can remain viable in dust or on fomites for up to 6 mo. Transmission through contaminated milk and through an infected food handler has been proved or suspected.
In the 1920s, >125,000 diphtheria cases, with 10,000 deaths, were reported annually in the United States, with the highest fatality rates among very young and elderly persons. The incidence then began to decrease and, with widespread use of diphtheria toxoid in the United States after World War II, declined steadily through the late 1970s. Since then, ≤5 cases have occurred annually in the United States, with no epidemics of respiratory tract diphtheria. Similar decreases occurred in Europe. Despite the worldwide decrease in disease incidence, diphtheria remains endemic in many developing countries with poor immunization rates against diphtheria.
When diphtheria was endemic, it primarily affected children <15 yr old. Since the introduction of toxoid immunization, the disease has shifted to adults who lack natural exposure to toxigenic C. diphtheriae in the vaccine era and have low rates of booster immunization. In the 27 sporadic cases of respiratory tract diphtheria reported in the United States in the 1980s, 70% occurred among persons >25 yr old. The largest outbreak of diphtheria in the developed world since the 1960s occurred from 1990–1996 in the newly independent countries of the former Soviet Union, involving >150,000 cases in 14 countries. Of these, >60% of cases occurred in individuals >14 yr old. Case fatality rates ranged from 3–23% by country. Factors contributing to the epidemic included a large population of underimmunized adults, decreased childhood immunization rates, population migration, crowding, and failure to respond aggressively during early phases of the epidemic. Cases of diphtheria among travelers from these endemic areas were transported to many countries in Europe.
Most proven cases of respiratory tract diphtheria in the United States in the 1990s were associated with importation of toxigenic C. diphtheriae, although clonally related toxigenic C. diphtheriae has persisted in this country and Canada for at least 25 yr. World Health Organization (WHO) surveillance reports indicate that most cases of diphtheria worldwide occur in the Southeast Asia and Africa regions. In Europe, increasing reports of respiratory and systemic infections have been attributed to C ulcerans ; animal contact is the predominant risk factor.
Cutaneous diphtheria, a curiosity when diphtheria was common, accounted for more than 50% of reported C. diphtheriae isolates in the United States by 1975. This indolent local infection, compared with mucosal infection, is associated with more prolonged bacterial shedding, greater contamination of the environment, and increased transmission to the pharynx and skin of close contacts. Outbreaks are associated with homelessness, crowding, poverty, alcoholism, poor hygiene, contaminated fomites, underlying dermatosis, and introduction of new strains from exogenous sources. It is no longer a tropical or subtropical disease; 1,100 C. diphtheriae infections were documented in a neighborhood in Seattle (site of the last major U.S. outbreak), from 1971–1982; 86% were cutaneous, and 40% involved toxigenic strains. Cutaneous diphtheria is an important source for toxigenic C. diphtheriae in the United States, and its importation is frequently the source for subsequent sporadic cases of respiratory tract diphtheria. Cutaneous diphtheria caused by C. ulcerans from travel to tropical countries or animal contact has been increasingly reported.
Both toxigenic and nontoxigenic C. diphtheriae cause skin and mucosal infection and can rarely cause focal infection after bacteremia. The organism usually remains in the superficial layers of skin lesions or respiratory tract mucosa, inducing local inflammatory reaction. The major virulence of the organism lies in its ability to produce a potent polypeptide exotoxin, which inhibits protein synthesis and causes local tissue necrosis and resultant local inflammatory response. Within the first few days of respiratory tract infection (usually in the pharynx), a dense necrotic coagulum of organisms, epithelial cells, fibrin, leukocytes, and erythrocytes forms, initially white and advancing to become a gray-brown, leather-like adherent pseudomembrane ( diphtheria is Greek for leather). Removal is difficult and reveals a bleeding edematous submucosa. Paralysis of the palate and hypopharynx is an early local effect of diphtheria toxin. Toxin absorption can lead to systemic manifestations: kidney tubule necrosis, thrombocytopenia, cardiomyopathy, and demyelination of nerves. Because the latter 2 complications can occur 2-10 wk after mucocutaneous infection, the pathophysiology in some cases is suspected to be immunologically mediated.
The manifestations of C. diphtheriae infection are influenced by the anatomic site of infection, the immune status of the host, and the production and systemic distribution of toxin.
In a classic description of 1,400 cases of diphtheria in California (1954), the primary focus of infection was the tonsils or pharynx (94%), with the nose and larynx the next 2 most common sites. After an average incubation period of 2-4 days (range 1-10 days), local signs and symptoms of inflammation develop. Infection of the anterior nares is more common among infants and causes serosanguineous, purulent, erosive rhinitis with membrane formation. Shallow ulceration of the external nares and upper lip is characteristic. In tonsillar and pharyngeal diphtheria , sore throat is the universal early symptom. Only half of patients have fever, and fewer have dysphagia, hoarseness, malaise, or headache. Mild pharyngeal injection is followed by unilateral or bilateral tonsillar membrane formation, which can extend to involve the uvula (which may cause toxin-mediated paralysis), soft palate, posterior oropharynx, hypopharynx, or glottic areas ( Fig. 214.1 ). Underlying soft tissue edema and enlarged lymph nodes can cause a bull-neck appearance. The degree of local extension correlates directly with profound prostration, bull-neck appearance, and fatality due to airway compromise or toxin-mediated complications ( Fig. 214.2 ).
The characteristic adherent membrane, extension beyond the faucial area, dysphagia, and relative lack of fever help differentiate diphtheria from exudative pharyngitis caused by Streptococcus pyogenes or Epstein-Barr virus. Vincent angina, infective phlebitis with thrombosis of the jugular veins (Lemierre syndrome), and mucositis in patients undergoing cancer chemotherapy are usually differentiated by the clinical setting. Infection of the larynx, trachea, and bronchi can be primary or a secondary extension from the pharyngeal infection. Hoarseness, stridor, dyspnea, and croupy cough are clues. Differentiation from bacterial epiglottitis, severe viral laryngotracheobronchitis, and staphylococcal or streptococcal tracheitis hinges partially on the relative paucity of other signs and symptoms in patients with diphtheria and primarily on visualization of the adherent pseudomembrane at laryngoscopy and intubation.
Patients with laryngeal diphtheria are at significant risk for suffocation because of local soft tissue edema and airway obstruction by the diphtheria membrane, a dense cast of respiratory epithelium, and necrotic coagulum. Establishment of an artificial airway and resection of the pseudomembrane can be lifesaving, but further obstructive complications are common, and systemic toxic complications are inevitable.
Classic cutaneous diphtheria is an indolent, nonprogressive infection characterized by a superficial, ecthyma-like, nonhealing ulcer with a gray-brown membrane. Diphtheria skin infections cannot always be differentiated from streptococcal or staphylococcal impetigo, and these conditions frequently coexist. In most cases, a primary process, such as dermatosis, laceration, burn, bite, or impetigo, becomes secondarily infected with C. diphtheriae. Extremities are more often affected than the trunk or head. Pain, tenderness, erythema, and exudate are typical. Local hyperesthesia or hypesthesia is unusual. Respiratory tract colonization or symptomatic infection with toxic complications occurs in the minority of patients with cutaneous diphtheria. Among infected adults in the Seattle outbreak, 3% with cutaneous infections and 21% with symptomatic nasopharyngeal infection, with or without skin involvement, demonstrated toxic myocarditis, neuropathy, or obstructive respiratory tract complications. All had received at least 20,000 units of equine antitoxin at the time of hospitalization.
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