Diphtheria is a nasopharyngeal and skin infection caused by Corynebacterium diphtheriae. Toxigenic strains of C. diphtheriae produce a protein toxin that causes systemic toxicity, myocarditis, and polyneuropathy. The toxin is associated with the formation of pseudomembranes in the pharynx during respiratory diphtheria. While toxigenic strains most frequently cause pharyngeal diphtheria, nontoxigenic strains commonly cause cutaneous disease.
C. diphtheriae is a gram-positive bacillus that is unencapsulated, nonmotile, and nonsporulating. The organism was first identified microscopically in 1883 by Klebs and a year later was isolated in pure culture by Löffler in Robert Koch’s laboratory. The bacteria have a characteristic club-shaped bacillary appearance and typically form clusters of parallel rays, or palisades, that are referred to as “Chinese characters.” The specific laboratory media recommended for the cultivation of C. diphtheriae rely upon tellurite, colistin, or nalidixic acid for the organism’s selective isolation from other autochthonous pharyngeal microbes. C. diphtheriae may be isolated from individuals with both nontoxigenic (tox–) and toxigenic (tox+) phenotypes. Uchida and Pappenheimer demonstrated that corynebacteriophage beta carries the structural gene tox, which encodes diphtheria toxin, and that a family of closely related corynebacteriophages are responsible for toxigenic conversion of tox– C. diphtheriae to the tox+ phenotype. Moreover, lysogenic conversion from a nontoxigenic to a toxigenic phenotype has been shown to occur in situ. Growth of toxigenic strains of C. diphtheriae under iron-limiting conditions leads to the optimal expression of diphtheria toxin and is believed to be a pathogenic mechanism during human infection.
While in many regions diphtheria has been controlled in recent years with effective vaccination, there have been sporadic outbreaks in the United States and Europe. Diphtheria is still common in the Caribbean, Latin America, and the Indian subcontinent, where mass immunization programs are not enforced. Large-scale epidemics of diphtheria have occurred in the post-Soviet independent states. Additional outbreaks have been reported in Algeria, China, and Ecuador.
C. diphtheriae is transmitted via the aerosol route, usually during close contact with an infected person. There are no significant reservoirs other than humans. The incubation period for respiratory diphtheria is 2–5 days, but disease onset has occurred as late as 10 days after exposure. Prior to the vaccination era, most individuals over the age of 10 were immune to C. diphtheriae; infants were protected by maternal IgG antibodies but became susceptible after ~6 months of age. Thus, the disease primarily affected children and nonimmune young adults. In temperate regions, respiratory diphtheria occurs year-round but is most common during winter months.
The development of diphtheria antitoxin in 1898 by von Behring and of the diphtheria toxoid vaccine in 1924 by Ramon led to the near-elimination of diphtheria in Western countries. The annual incidence rate in the United States peaked in 1921 at 191 cases per 100,000 population. In contrast, since 1980, the annual figure in the United States has been <5 cases per 100,000. Nevertheless, pockets of colonization persist in North America, particularly in South Dakota, Ontario, and recently the state of Washington. Immunity to diphtheria induced by childhood vaccination gradually decreases in adulthood. An estimated 30% of men 60–69 years old have antitoxin titers below the protective level. In addition to older age and lack of vaccination, risk factors for diphtheria outbreaks include alcoholism, low socioeconomic status, crowded living conditions, and Native American ethnic background. An outbreak of diphtheria in Seattle, Washington, between 1972 and 1982 comprised 1100 cases, most of which were cutaneous. During the 1990s in the states of the former Soviet Union, a much larger diphtheria epidemic included more than 150,000 cases and more than 5000 deaths. Clonally related toxigenic C. diphtheriae strains of the ET8 complex were associated with this outbreak. Given that the ET8 complex expressed a toxin against which the prevalent diphtheria toxoid vaccine was effective, the epidemic was attributed to failure of the public health infrastructure to effectively vaccinate the population. Beginning in 1998, this epidemic was controlled by mass vaccination programs. During the epidemic, the incidence rate was high among individuals between 16 and 50 years of age. Socioeconomic instability, migration, deteriorating public health programs, frequent vaccine shortages, delayed implementation of vaccination and treatment in response to cases, and lack of public education and awareness were contributing factors.
Significant outbreaks of diphtheria and diphtheria-related mortality continue to be reported from many developing countries, particularly in Africa and Asia. Statistics collected by the World Health Organization indicated the occurrence of ~7000 reported diphtheria cases in 2008 and ~5000 diphtheria deaths in 2004. Although ~82% of the global population has been adequately vaccinated, only 26% of countries have successfully vaccinated >80% of individuals in all districts.
Cutaneous diphtheria is usually a secondary infection that follows a primary skin lesion due to trauma, allergy, or autoimmunity. Most often, these isolates lack the tox gene and thus do not express diphtheria toxin. In tropical latitudes, cutaneous diphtheria is more common than respiratory diphtheria. In contrast to respiratory disease, cutaneous diphtheria is not reportable in the United States. Nontoxigenic strains of C. diphtheriae have also been associated with pharyngitis in Europe, causing outbreaks among men who have sex with men and persons who use illicit IV drugs.
PATHOGENESIS AND IMMUNOLOGY
Diphtheria toxin produced by tox+ 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, in sensitive species (e.g., guinea pigs and humans, but not mice or rats), has a 50% lethal dose of ~100 ng/kg of body weight. The toxin is produced in the pseudomembranous lesion and is taken up in the bloodstream, from which it is distributed to all organ systems in the body. 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 endosomal compartment. In vitro, the toxin may be separated into two chains by digestion with 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 irreversible inhibition of protein synthesis by NAD+-dependent ADP-ribosylation of elongation factor 2. The eventual result is the death of the cell.
In 1926, Ramon at the Institut Pasteur found that formalinization of diphtheria toxin resulted in the production of a nontoxic but highly immunogenic diphtheria toxoid. Subsequent studies showed that immunization with diphtheria toxoid elicited antibodies that neutralized the toxin and prevented most disease manifestations. In the 1930s, mass immunization of children and susceptible adults with diphtheria toxoid commenced in the United States and Europe.
Individuals with a diphtheria antitoxin titer of >0.01 U/mL are at low risk of disease. In populations where a majority of individuals have protective antitoxin titers, the carrier rate for toxigenic strains of C. diphtheriae decreases and the overall risk of diphtheria among susceptible individuals is reduced. Nevertheless, individuals with nonprotective titers may contract diphtheria through either travel or exposure to individuals who have recently returned from regions where the disease is endemic.
Characteristic pathologic findings of diphtheria include mucosal ulcers with a pseudomembranous coating composed of an inner band of fibrin and a luminal band of neutrophils. Initially white and firmly adherent, in advanced diphtheria the pseudomembranes turn gray or even green or black as necrosis progresses. Mucosal ulcers result from toxin-induced necrosis of the epithelium accompanied by edema, hyperemia, and vascular congestion of the submucosal base. A significant fibrinosuppurative exudate from the ulcer develops into the pseudomembrane. Ulcers and pseudomembranes in severe respiratory diphtheria may extend from the pharynx into medium-sized bronchial airways. Expanding and sloughing membranes may result in fatal airway obstruction.
APPROACH TO THE PATIENT: Diphtheria
Diphtheria, though rare in the United States and other developed countries, should be considered when a patient has severe pharyngitis, particularly when there is difficulty swallowing, respiratory compromise, or signs of systemic disease (e.g., myocarditis or generalized weakness). The leading causes of pharyngitis are respiratory viruses (rhinoviruses, influenza viruses, parainfluenza viruses, coronaviruses, adenoviruses; ~25% of cases), group A streptococci (15–30%), group C streptococci (~5%), atypical bacteria such as Mycoplasma pneumoniae and Chlamydia pneumoniae (15–20% in some series), and other viruses such as herpes simplex virus (~4%) and Epstein-Barr virus (<1% in infectious mononucleosis). Less common causes are acute HIV infection, gonorrhea, fusobacterial infection (e.g., Lemierre’s syndrome), thrush due to Candida albicans or other Candida species, and diphtheria. The presence of a pharyngeal pseudomembrane or an extensive exudate should prompt consideration of diphtheria (Figure 47-1).
Respiratory diphtheria due to toxigenic C. diphtheriae producing exudative pharyngitis in a 47-year-old female patient displaying neck edema and a pseudomembrane extending from the uvula to the pharyngeal wall. The characteristic white pseudomembrane is caused by diphtheria toxin–mediated necrosis of the respiratory epithelial layer, producing a fibrinous coagulative exudate. Submucosal edema adds to airway narrowing. The pharyngitis is acute in onset, and respiratory obstruction from the pseudomembrane may occur in severe cases. Inoculation of pseudomembrane fragments or submembranous swabs onto Löffler’s or tellurite selective medium reveals C. diphtheriae. (Photograph by P. Strebel, MD, used by permission. From R. Kadirova et al: J Infect Dis 181:S110, 2000. With permission of Oxford University Press.)
The clinical diagnosis of diphtheria is based on the constellation of sore throat; adherent tonsillar, pharyngeal, or nasal pseudomembranous lesions; and low-grade fever. In addition, diagnosis requires the isolation of C. diphtheriae or histopathologic isolation of compatible gram-positive organisms. The Centers for Disease Control and Prevention (CDC) recognizes confirmed respiratory diphtheria (laboratory proven or epidemiologically linked to a culture-confirmed case) and probable respiratory diphtheria (clinically compatible but not laboratory proven or epidemiologically linked). Carriers are defined as individuals who have positive cultures for C. diphtheriae and who either are asymptomatic or have symptoms but lack pseudomembranes. Most patients seek medical care for sore throat and fever several days into the illness. Occasionally, weakness, dysphagia, headache, and voice change are the initial manifestations. Neck edema and difficulty breathing are evident in more advanced cases and carry a poor prognosis.
The systemic manifestations of diphtheria stem from the effects of diphtheria toxin and include weakness as a result of neurotoxicity and cardiac arrhythmias or congestive heart failure due to myocarditis. Most commonly, the pseudomembranous lesion is located in the tonsillopharyngeal region. Less commonly, the lesions are located in the larynx, nares, and trachea or bronchial passages. Large pseudomembranes are associated with severe disease and a poor prognosis. A few patients develop massive swelling of the tonsils and present with “bull-neck” diphtheria, which results from massive edema of the submandibular and paratracheal region and is further characterized by foul breath, thick speech, and stridorous breathing. The diphtheritic pseudomembrane is gray or whitish and sharply demarcated. Unlike the exudative lesion associated with streptococcal pharyngitis, the pseudomembrane in diphtheria is tightly adherent to the underlying tissues. Attempts to dislodge the membrane may cause bleeding. Hoarseness suggests laryngeal diphtheria, in which laryngoscopy may be diagnostically helpful.
This dermatosis is characterized by punched-out ulcerative lesions with necrotic sloughing or pseudomembrane formation (Figure 47-2). The diagnosis requires cultivation of C. diphtheriae from lesions, which most commonly occur on the lower and upper extremities, head, and trunk.
Cutaneous diphtheria due to nontoxigenic C. diphtheriae on the lower extremity. (From the Centers for Disease Control and Prevention.)
Infections due to non-diphtheriae Corynebacterium species and nontoxigenic C. diphtheriae
Non-diphtheriae species of Corynebacterium and related genera (discussed below) as well as nontoxigenic strains of C. diphtheriae itself have been found in bloodstream and respiratory infections, often in individuals with immunosuppression or chronic respiratory disease. These organisms can cause disease manifestations and should not necessarily be dismissed as colonizers.
Other clinical manifestations
C. diphtheriae causes rare cases of endocarditis and septic arthritis, most often in patients with preexisting risk factors, such as abnormal cardiac valves, injection drug use, or cirrhosis.
Airway obstruction poses a significant early risk in patients presenting with advanced diphtheria. Pseudomembranes may slough and obstruct the airway or may advance to the larynx or into the tracheobronchial tree. Children are particularly prone to obstruction because of their small airways.
Polyneuropathy and myocarditis are late toxic manifestations of diphtheria. During a diphtheria outbreak in the Kyrgyz Republic in 1999, myocarditis was found in 22% and neuropathy in 5% of 656 hospitalized patients. The mortality rate was 7% among patients with myocarditis as opposed to 2% among those without myocardial manifestations. The median time to death in hospitalized patients was 4.5 days. Myocarditis is typically associated with dysrhythmia of the conduction tract and dilated cardiomyopathy.
Polyneuropathy is seen 3–5 weeks after the onset of diphtheria and has a slow indolent course. However, patients may develop severe and prolonged neurologic abnormalities. The disorders typically occur in the mouth and neck, with lingual or facial numbness as well as dysphonia, dysphagia, and cranial nerve paresthesias. More ominous signs include weakness of respiratory and abdominal muscles and paresis of the extremities. Sensory manifestations and sensory ataxia also are observed. Cranial nerve dysfunction typically precedes disturbances of the trunk and extremities because of proximity to the site of infection. Autonomic dysfunction also is associated with polyneuropathy and can lead to hypotension. Polyneuropathy is typically reversible in patients who survive the acute phase.
Other complications of diphtheria include pneumonia, renal failure, encephalitis, cerebral infarction, pulmonary embolism, and serum sickness from antitoxin therapy.
The diagnosis of diphtheria is based on clinical signs and symptoms plus laboratory confirmation. Respiratory diphtheria should be considered in patients with sore throat, pharyngeal exudates, and fever. Other symptoms may include hoarseness, stridor, or palatal paralysis. The presence of a pseudomembrane should prompt strong consideration of diphtheria. Once a clinical diagnosis of diphtheria is made, diphtheria antitoxin should be obtained and administered as rapidly as possible.
Laboratory diagnosis of diphtheria is based either on cultivation of C. diphtheriae or toxigenic Corynebacterium ulcerans from the site of infection or on the demonstration of local lesions with characteristic histopathology. Corynebacterium pseudodiphtheriticum, a nontoxigenic organism, is a common component of the normal throat flora and does not pose a significant risk. Throat samples should be submitted to the laboratory for culture with the notation that diphtheria is being considered. This information should prompt cultivation on special selective medium and subsequent biochemical testing to differentiate C. diphtheriae from other nasopharyngeal commensal corynebacteria. All laboratory isolates of C. diphtheriae, including nontoxigenic strains, should be submitted to the CDC.
A diagnosis of cutaneous diphtheria requires laboratory confirmation since the lesions are not characteristic and are indistinguishable from other dermatoses. Diphtheritic ulcers occasionally—but not consistently—have a punched-out appearance (Fig. 47-2). Patients in whom cutaneous diphtheria is identified should have the nasopharynx cultured for C. diphtheriae. The laboratory medium for cutaneous diphtheria specimens is the same as that used for respiratory diphtheria: Löffler’s or Tinsdale’s selective medium in addition to nonselective medium such as blood agar. As has been mentioned, respiratory diphtheria remains a notifiable disease in the United States, whereas cutaneous diphtheria is not.
TREATMENT Diphtheria DIPHTHERIA ANTITOXIN
Prompt administration of diphtheria antitoxin is critical in the management of respiratory diphtheria. Diphtheria antitoxin, a horse antiserum, is effective in reducing the extent of local disease as well as the risk of complications of myocarditis and neuropathy. Rapid institution of antitoxin therapy is also associated with a significant reduction in mortality risk. Because diphtheria antitoxin cannot neutralize cell-bound toxin, prompt initiation is important. This product, which is no longer commercially available in the United States, can be obtained from the CDC by calling the Bacterial Vaccine Preventable Disease Branch of the National Immunization Program at 404-639-8257 (8:00 a.m. to 4:30 p.m., U.S. Eastern time) or, at other hours, the Emergency Operations Center at 770-488-7100; the relevant website is www.cdc.gov/diphtheria/dat.html. The current protocol for the use of diphtheria antitoxin involves a test dose to rule out immediate hypersensitivity. Patients who demonstrate hypersensitivity require desensitization before a full therapeutic dose of antitoxin is administered. ANTIMICROBIAL THERAPY
Antibiotics are used in the management of diphtheria primarily to prevent transmission to susceptible contacts. Antibiotics also prevent further toxin production and reduce the severity of local infection. Recommended treatment options for patients with respiratory diphtheria are as follows:
Procaine penicillin G, 600,000 U IM q12h (for children: 12,500–25,000 U/kg IM q12h) until the patient can swallow comfortably; then oral penicillin V, 125–250 mg qid to complete a 14-day course
Erythromycin, 500 mg IV q6h (for children: 40–50 mg/kg per day IV in two or four divided doses) until the patient can swallow comfortably; then 500 mg PO qid to complete a 14-day course
A clinical study in Vietnam found that penicillin was associated with a more rapid resolution of fever and a lower rate of bacterial resistance than erythromycin; however, relapses were more common in the penicillin group. Erythromycin therapy targets protein synthesis and thus offers the presumed benefit of stopping toxin synthesis more quickly than a cell wall–active β-lactam agent. Alternative therapeutic agents for patients who are allergic to penicillin or cannot take erythromycin include rifampin and clindamycin. Eradication of C. diphtheriae should be documented after antimicrobial therapy is complete. A repeat throat culture 2 weeks later is recommended. For patients in whom the organism is not eradicated after a 14-day course of erythromycin or penicillin, an additional 10-day course followed by repeat culture is recommended. Drug-resistant strains of C. diphtheriae exist, and several reports have described multidrug-resistant strains, predominantly in Southeast Asia. Drug resistance should be considered when efforts at pathogen eradication fail.
Cutaneous diphtheria should be treated as described above for respiratory disease. Individuals infected with toxigenic strains should receive antitoxin. It is important to treat the underlying cause of the dermatoses in addition to the superinfection with C. diphtheriae.
Patients who recover from respiratory or cutaneous diphtheria should have antitoxin levels measured. If diphtheria antitoxin has been administered, this test should be performed 6 months later. Patients who recover from respiratory or cutaneous diphtheria should receive the appropriate vaccine to ensure the development of protective antibody titers. MANAGEMENT STRATEGIES
Patients in whom diphtheria is suspected should be hospitalized in respiratory isolation rooms, with close monitoring of cardiac and respiratory function. A cardiac workup is recommended to assess the possibility of myocarditis. In patients with extensive pseudomembranes, an anesthesiology or an ear, nose, and throat consultation is recommended because of the possible need for tracheostomy or intubation. In some settings, pseudomembranes can be removed surgically. Treatment with glucocorticoids has not been shown to reduce the risk of myocarditis or polyneuropathy.
Fatal pseudomembranous diphtheria typically occurs in patients with nonprotective antibody titers and in unimmunized patients. The pseudomembrane may actually increase in size from the time it is first noted. Risk factors for death include bullneck diphtheria; myocarditis with ventricular tachycardia; atrial fibrillation; complete heart block; an age of >60 years or <6 months; alcoholism; extensive pseudomembrane elongation; and laryngeal, tracheal, or bronchial involvement. Another important predictor of fatal outcome is the interval between the onset of local disease and the administration of antitoxin. Cutaneous diphtheria has a low mortality rate and is rarely associated with myocarditis or peripheral neuropathy.
Sustained campaigns for vaccination of children and adequate boosting vaccination of adults are responsible for the exceedingly low incidence of diphtheria in most developed nations. Currently, diphtheria toxoid vaccine is coadministered with tetanus vaccine (with or without acellular pertussis). DTaP (a full-level diphtheria and tetanus toxoids and acellular pertussis vaccine) is currently recommended for children up to the age of 7; DTaP replaced the earlier whole-cell pertussis vaccine DTP in 1997. Tdap is a tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine formulated for adolescents and adults. Tdap was licensed for use in the United States in 2005 and is the recommended booster vaccine for children 11–12 years old and the recommended catch-up vaccine for children 7–10 and 13–18 years of age. It is recommended that all adults (i.e., persons >19 years old) receive a single dose of Tdap if they have not received it previously, regardless of the interval since the last dose of Td (tetanus and reduced-dose diphtheria toxoids, adsorbed). Tdap vaccination is a priority for health care workers, pregnant women, adults anticipating contact with infants, and adults not previously vaccinated for pertussis. Adults who have received acellular pertussis vaccine should continue to receive decennial Td booster vaccinations. The vaccine schedule is detailed in Chap. 5.
Prophylaxis administration to contacts
Close contacts of diphtheria patients should undergo throat culture to determine whether they are carriers. After samples for throat culture are obtained, antimicrobial prophylaxis should be considered for all contacts, even those whose cultures are negative. The options are 7–10 days of oral erythromycin or one dose of IM benzathine penicillin G (1.2 million units for persons ≥6 years of age or 600,000 units for children <6 years of age).
Contacts of diphtheria patients whose immunization status is uncertain should receive the appropriate diphtheria toxoid–containing vaccine. The Tdap vaccine (rather than Td) is now the booster vaccine of choice for adults who have not recently received an acellular pertussis–containing vaccine. Carriers of C. diphtheriae in the community should be treated and vaccinated when identified.