Corynebacterium diphtheriae

The Pathogen

Corynebacterium species are aerobic, nonencapsulated, nonspore-forming, mostly nonmotile, pleomorphic gram-positive bacilli. Isolation is enhanced using selective media (e.g., cystine-tellurite blood agar) that inhibit the growth of competing organisms and, when reduced by C. diphtheriae, produce colonies that appear grey to black. Modified Tinsdale medium and Löffler or Pai slants are additional effective enrichment media. Growth occurs within 48 hours; Gram staining of typical colonies from Löffler or Pai media can confirm a presumptive identification. Three phenotypes ( mitis, gravis, and intermedius ), each capable of causing diphtheria, are distinguished by colony morphology, hemolysis, and fermentation reactions. A lysogenic bacteriophage that encodes for production of exotoxin does not confer an essential protein to the bacterium, but factors other than toxin production can cause virulence and facilitate the spread of infection.

Production of diphtheria toxin can be demonstrated in vitro by use of an agar well or antitoxin membrane immunoprecipitation technique (Elek test), or by in vivo toxin neutralization tests in the guinea pig. ^, Investigational polymerase chain reaction (PCR) tests detect the presence of genes for both A and B toxin subunits, but do not prove toxin production directly. Toxigenic strains are indistinguishable by colony type, microscopy, or biochemical tests. Expression of toxin is enhanced in vitro by depletion of nutrient or iron or by exposure to ultraviolet light. Nontoxigenic C. diphtheriae can be converted to toxigenic strains by lysogenic infection. Studies of outbreaks in which molecular techniques were used suggest that indigenous nontoxigenic C. diphtheriae strains can be rendered toxigenic, producing clinical diphtheria, after importation of single cases of toxigenic C. diphtheriae. Nondiphtheria strains of Corynebacterium (e.g., C. ulcerans ) can sometimes produce diphtheria toxin and cause a respiratory diphtheria-like illness. ^,

Epidemiology

Coryneform bacteria (“diphtheroids”) are ubiquitous in nature. They are found on human skin and mucous membranes, on plants, in soil, and in freshwater and saltwater. Humans have been considered the sole reservoir of C. diphtheriae while, recently, a novel strain was isolated from cats with unknown epidemiologic implications . The primary modes of spread are airborne respiratory droplets and direct contact with respiratory secretions or exudate from skin lesions. Skin infection, or carriage, can be the silent reservoir of toxigenic diphtheria. Viability in dust and on fomites for up to 6 months has unknown epidemiologic significance. Transmission of toxigenic non diphtheria strain by means of animals or contaminated milk has been proved or suspected. ^,

Diphtheria occurs worldwide. In temperate climates, the incidence is higher during the colder months. While the number of cases has been decreasing globally, the disease remains endemic in many resource-poor countries with inadequate immunization rates, occurring predominantly in poor living conditions. Between 2001 and 2015, almost half of the cases reported globally originated from India. In industrialized countries, the main risk factor for acquisition of toxigenic C. diphtheriae is travel to endemic areas (Asia, South Pacific, Eastern Europe) or laboratory exposure. Concerns for re-emergence stem from the description of cases among refugees or migrant workers in countries where diphtheria may not be recognized readily as a diagnosis. ^,

Before 1930, >125,000 cases and 10,000 deaths caused by diphtheria were reported annually in the US (incidence, 100–200 cases per 100,000). The highest fatality rates occurred among people <5 years of age and >40 years of age. The widespread use of diphtheria toxoid vaccine in the US after World War II produced a steady decline in the incidence of diphtheria, to 0.001 per 100,000 population. In recent years, the few reported respiratory cases have been imported.

Although immunization does not prevent respiratory or cutaneous carriage or infection with toxigenic C. diphtheriae, neutralization of toxin diminishes local tissue spread, necrosis, multiplication, and transmission, thereby providing herd immunity. It is estimated that 70%–80% of a population must be immunized to prevent epidemic spread. Even with the low rate of circulating toxigenic C. diphtheriae in most resource-rich countries, under-immunized subgroups of the population would be at risk if the organism was introduced. In a multicenter European study, screening of upper respiratory specimen cultures revealed both toxigenic and nontoxigenic strains of C. diphtheriae, indicating carriage in highly vaccinated populations.

Low levels of antitoxin in some populations may reflect relatively poor rates of administration of booster diphtheria vaccines after primary immunization in childhood. The National Immunization Survey in the US has demonstrated that coverage with at least 3 doses of diphtheria toxoid among children 19–35 months old has been approximately 95% for more than a decade. However, in serosurveys in the US and western European countries, where childhood immunization is universal, 20% to >60% of people were found to lack protective antitoxin levels (antitoxin level >0.01 IU/mL), with particularly low levels among the elderly. ^, The recent epidemiology of diphtheria demonstrates a shift from endemic disease in childhood to outbreaks in adults. In 27 sporadic cases of respiratory tract diphtheria in the US in the 1980s, 70% occurred in people >25 years of age. A similar shift of the epidemiology of diphtheria to adult cases has been identified in Europe.

Cutaneous diphtheria is considered to be central to the changing epidemiology of diphtheria. Cutaneous infection is infrequently associated with toxic complications and is caused by toxigenic and nontoxigenic strains, often in association with other bacteria. In contrast to respiratory tract infection, cutaneous diphtheria is associated with prolonged bacterial shedding, increased environmental contamination, and increased transmission to close contacts. Outbreaks of cutaneous diphtheria have been associated with homelessness, crowding, poverty, alcoholism, poor hygiene, contaminated fomites, underlying dermatosis, and introduction of new strains from exogenous sources. Cutaneous diphtheria has been considered a reservoir for toxigenic C. diphtheriae and has been a frequent mode of importation of source cases for sporadic respiratory tract diphtheria. While cutaneous diphtheria was not notifiable in the US between 1980 and 2018, a recently revised case definition calls for reporting of cases with toxin-producing disease, irrespective of site of infection.

Other than the sporadic imported cases in resource-rich countries, ^, there are concerns for a resurgence of diphtheria in the form of outbreaks in different places of the world. In the 1990s, the largest outbreak of diphtheria in recent years occurred in the Newly Independent States of the former Soviet Union; >150,000 cases occurred within 6 years in 14 of the 15 states. Case-fatality rates ranged from 3% to 23% by state, and >60% of cases occurred among people >14 years. Factors contributing to the epidemic included a large population of susceptible (i.e., under-immunized) adults, decreased childhood immunization, population migration, crowding, and a failure to respond aggressively during early phases of the epidemic. Attempts to control the epidemic with childhood immunization alone failed, whereas mass immunization of both children and adults was successful. Cases of diphtheria among travelers were transported to many countries in Europe. Recent outbreaks in Indonesia and among refugees in Bangladesh resulted in hundreds of cases. ^, Even smaller scale outbreaks, such as among the indigenous people of Venezuela, highlight the risk posed by pockets of under-immunization in control of diphtheria.

Pathogenesis

Both toxigenic and nontoxigenic C. diphtheriae organisms cause skin and mucosal infection in addition to rare distant infection after bacteremia. The organisms remain confined to superficial layers of skin lesions or respiratory mucosa and induce a local inflammatory reaction. The major virulence factor is a potent 62-kd polypeptide exotoxin that consists of a binding segment A and an active segment B which, when cleaved, is internalized, activating transfer RNA translocase and preventing the addition of amino acids during protein synthesis. Within the first few days of respiratory tract infection, a dense, necrotic “pseudomembrane” forms, consisting of organisms, epithelial cells, fibrin, leukocytes, and erythrocytes. The pseudomembrane advances and becomes adherent. Removal is difficult and reveals a bleeding, edematous submucosa. Early local effects of the toxin include paralysis of the palate and hypopharynx. Absorption and hematogenous dissemination of the toxin can lead to necrosis of the kidney tubules and hepatic parenchyma, amegakaryocytic thrombocytopenia, myocardiopathy, and demyelinating neuropathy. Cardiomyopathy and neuropathy occur 2–10 weeks after the initial mucocutaneous infection and may involve an immune-mediated pathophysiology in addition to delayed appearance of toxic tissue damage.

Clinical Manifestations

Respiratory Tract Diphtheria

In a classic description of 1400 cases of diphtheria, infection involved the tonsils or pharynx in 94%; the nose and larynx were the next two most common sites. After an average incubation period of 2–4 days, local signs and symptoms of inflammation develop. Fever is low grade or absent. Infection of the anterior nares (more common in infants) causes serosanguinous, erosive rhinitis with membrane formation. Shallow ulceration of the external nares and upper lip is characteristic. Sore throat is a universal early symptom of tonsillar or pharyngeal diphtheria, but only 50% 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 extends off tonsillar tissues to variably affect the uvula, soft palate, posterior oropharynx, hypopharynx, and glottic areas ( Fig. 130.1 ). Underlying soft tissue edema and enlarged lymph nodes can cause cervical swelling (e.g., bullneck), characterized by obliteration of the borders of the mandible, sternocleidomastoid muscle, and clavicle by brawny, pitting, warm, tender, but nonerythematous edema. The degree of toxin extension correlates directly with symptoms of prostration, bullneck, airway compromise, and subsequent toxin-mediated complications in distant organs. A patient with laryngeal diphtheria is highly prone to acute airway compromise as a result of local edema and the formation of the pseudomembrane. Establishment of an artificial airway and resection of pseudomembrane may be lifesaving.

The appearance of the leatherlike, adherent pseudomembrane, which extends beyond the faucial tonsillar area, and a relative lack of fever and dysphagia help distinguish diphtheria from the exudative pharyngitis caused by Streptococcus pyogenes, adenovirus, and Epstein-Barr virus. The absence of exanthem or ulcers elsewhere on the oral mucosa and tongue distinguishes diphtheria from infections arising from other viral causes. Vincent angina and Lemierre disease, phlebitis and thrombosis of the jugular veins, mucositis in patients undergoing cancer chemotherapy, and a faucial membrane after tonsillectomy usually are distinguished by the clinical setting. Diphtheritic infection of the larynx, trachea, or bronchi can be primary or can occur from secondary extension after nasal or pharyngeal infection; hoarseness, stridor, dyspnea, and a croupy cough are clues to infection of these sites. Differentiation from bacterial epiglottitis, severe viral laryngotracheobronchitis, and staphylococcal or streptococcal tracheitis hinges partially on the relative paucity of other signs and symptoms in a patient with diphtheria and primarily on visualization of an adherent pseudomembrane at the time of laryngobronchoscopy and intubation.

Cutaneous Diphtheria

Cutaneous diphtheria is usually an indolent, nonprogressive infection characterized by a superficial, ecthymic, nonhealing ulcer with a grey-brown membrane. Diphtheritic skin infection often cannot be distinguished from streptococcal or staphylococcal impetigo, and the conditions frequently coexist. In the Seattle outbreak, S. pyogenes was isolated in 73% of diphtheritic skin lesions. The role of C. diphtheriae as the cause of localized findings is not clear. Ulcers do not respond to antitoxin therapy, but infection elicits high antitoxin levels. In most cases, underlying dermatoses, lacerations, burns, bites, or impetigo have become secondarily contaminated. The extremities are affected more often than the trunk or head. Pain, tenderness, erythema, and exudate are typical. Local hyperesthesia or hypoesthesia can occur. Respiratory tract colonization or symptomatic infection, in addition to toxic complications, occur in a minority of patients with cutaneous diphtheria. Of the infected adults in Seattle, 3% of those with cutaneous infections (compared with 21% of those with symptomatic nasopharyngeal infection with or without skin involvement) had toxic myocarditis, neuropathy, or obstructive respiratory tract complications. All had received at least 20,000 units of equine antitoxin at the time of hospitalization.

Infection at Other Sites

C. diphtheriae occasionally causes infections at other mucocutaneous sites, such as the ear (otitis externa), eye (purulent and ulcerative conjunctivitis involving primarily palpebral areas), and genital tract (purulent and ulcerative vulvovaginitis). The clinical setting, ulceration, pseudomembrane formation, and submucosal bleeding help differentiate diphtheritic infection from other bacterial and viral causes.

Rare cases of septicemia caused by C. diphtheriae have been described, and such cases are often fatal. Sporadic cases of endocarditis occur, and clusters among intravenous drug users have been reported, ^, as have occasional cases in children living in endemic areas. ^, Notable clinical features are aggressive valvular destruction with associated pyogenic arthritis and major vascular complications (emboli and aneurysms) caused by the large size of vegetations; most complications have been caused by nontoxigenic strains. Most patients did not have respiratory tract symptoms. Although skin lesions were not described, skin is likely to have been the portal of entry. Sporadic cases of pyogenic arthritis, mainly caused by nontoxigenic strains, have been reported in adults and children.

Diphtheroids isolated from sterile body sites should not be dismissed as contaminants without careful consideration of the clinical setting, and isolates should be identified to the species level if validly associated with invasive disease. If C. diphtheriae is isolated, toxigenicity studies of the isolate should be completed and prophylaxis for contacts should be considered.

Toxic Myocardiopathy

Toxic myocardiopathy occurs in approximately 10%–25% of patients with diphtheria and is responsible for 50%–60% of deaths. Given wider availability of respiratory support, toxic myocardiopathy is currently considered the leading cause of death from diphtheria. Subtle signs of myocarditis may be detectable in many patients, especially in the elderly, but the risk of significant complications for an individual correlates directly with the extent and severity of exudative oropharyngeal disease and delays in administration of antitoxin.

Most often, the first evidence of cardiomyopathy is recognized in the second to third week of illness, as pharyngeal disease improves. However, cardiomyopathy can appear as early as the first week (in which case the likelihood of a fatal outcome is high) or insidiously, as late as the sixth week of illness. Tachycardia out of proportion to fever is common evidence of cardiac toxicity or autonomic nervous system dysfunction. A prolonged PR interval or ST-segment and T-wave changes are relatively frequent findings on an electrocardiogram, and dilated or hypertrophic cardiomyopathy frequently is observed on an echocardiogram. Single or progressive cardiac arrhythmias can occur, such as first-, second-, and third-degree heart block, atrioventricular dissociation, and ventricular tachycardia. Clinical congestive heart failure can have an insidious or acute onset. Elevation of the serum aspartate aminotransferase concentration closely parallels the severity of cardiac myonecrosis. Severe arrhythmia portends death. ^{, ,} Histologic postmortem findings can show a minor abnormality or diffuse myonecrosis with an acute inflammatory response. Except for survivors of more severe arrhythmias, who may have permanent conduction defects, patients usually recover completely from toxic myocardiopathy.

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