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| CECIL |
| TEXT BOOK of MEDICINE |
Section XXIII Infectious Diseases
| 315 DIPHTHERIA AND OTHER CORYNEBACTERIA INFECTIONS Roland W. Sutter • |
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DIPHTHERIA
Definition
Diphtheria is an acute infectious disease caused by Corynebacterium diphtheriae, a gram-positive bacillus. The organism primarily infects the respiratory tract, where it causes tonsillopharyngitis or laryngitis, or both (typically with a pseudomembrane), as well as the skin, where it is responsible for a variety of indolent lesions. If the infecting strain produces exotoxin, myocarditis and neuritis may ensue.
The Pathogen
C. diphtheriae is a member of a group of aerobic, nonmotile, unencapsulated, nonsporulating, pleomorphic gram-positive bacilli. Its name comes from the Greek korynee (meaning “club”), which describes the shape of the organism on stained smears with one end usually being wider, and diphtheria (meaning “leather hide”), for the characteristic adherent membrane. The genus Corynebacterium is characterized by bacilli that line up in parallel groups and bend when dividing to create “Chinese character” arrangements. Both nontoxigenic and toxigenic C. diphtheria strains exist. Toxigenicity is conferred when a nontoxigenic organism is infected with a beta-phage carrying the gene for the toxin (tox). C. diphtheriae has three biotypes—gravis, mitis, and intermedius—that are distinguished by colonial morphology and varying biochemical and hemolytic reactions. Strains may be distinguished for epidemiologic purposes by molecular techniques. Corynebacterium ulcerans can also produce classic diphtheria, including local respiratory tract and distal toxic complications.
Epidemiology
Humans are the only natural reservoir of C. diphtheriae, although the organism has occasionally been isolated from a variety of domestic and other animals. Spread occurs in close-contact settings through respiratory droplets or by direct contact with respiratory secretions or skin lesions. The organism survives for weeks and possibly months on environmental surfaces and in dust, and fomite transmission may occur. The majority of nasopharyngeal C. diphtheriae infections result in asymptomatic carriage, with clinical disease developing in only about one in seven individuals. However, asymptomatic carriers are important in maintaining transmission.
Diphtheria immunization protects against disease but does not prevent carriage. In the prevaccine era, respiratory disease dominated in temperate climates, with a fall/winter peak in incidence. Most individuals acquired natural immunity by the midteen years. Cutaneous disease is the predominant form of the disease in tropical countries, but over the past 2 decades, outbreaks of this form of diphtheria have occurred in the United States and Europe, typically in homeless and alcoholic inner-city adults.
Vaccination with diphtheria toxoid (formalin-treated toxin) was introduced in the 1920s. Immunization of children in an era when the majority of older individuals had natural immunity resulted in a dramatic drop in the incidence of diphtheria and an even more rapid decline in the proportion of toxigenic strains isolated, presumably because the selective advantage of the tox gene—promotion of greater replication and spread of the organism—is lost in an immune host. In most Western countries, toxigenic C. diphtheriae has virtually been eliminated. In the United States, reported cases fell from 147,991 in 1920, to 15,536 in 1940, to a total of 40 cases from 1980 to 1993. The absence of reported diphtheria cases in the United States in recent years, however, does not indicate that circulation of toxigenic C. diphtheriae has ceased. Investigations in a Northern Plains Indian community in North Dakota and First Nations communities in Ontario, Canada, suggested that C. diphtheriae strains might have circulated independently for more than 2 decades in these communities despite the absence of reported respiratory diphtheria cases.
Vaccine-induced immunity to diphtheria wanes with time, and there is a growing cohort of individuals with no natural diphtheria immunity. Serosurveys indicate that 20 to 60% of adults in industrialized countries have diphtheria antitoxin levels below minimal protective levels. A level of 0.01 IU/mL from an in vitro neutralization assay, the “gold standard” test, is considered the lower limit of protection. As long as a high proportion of the population remains susceptible, the danger of reintroduction or reemergence of toxigenic strains exists.
Since 1990 there has been a major resurgence of diphtheria in several countries of the former Soviet Union. In Russia, the number of reported cases rose from 593 in 1989 to 39,582 in 1994, with over two thirds of cases occurring in adults. Large-scale campaigns of mass administration of diphtheria toxoid to virtually the entire population in the affected new independent states of the former Soviet Union have since led to significant decreases in the incidence of diphtheria, from a peak of 50,449 cases in 1995, to 7197 cases in 1997, to pre-resurgence levels by the late 1990s (Fig. 315-1).
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| FIGURE 315-1 Reported diphtheria cases, worldwide and by European Region of the World Health Organization, 1980-2004. ▪ = total cases worldwide; ♦ = cases in European region of WHO. (Data from the World Health Organization.) |
Pathobiology
In classic respiratory diphtheria, C. diphtheriae colonizes the mucosal surface of the nasopharynx and multiplies locally without blood stream invasion. Released toxin causes local tissue necrosis with the formation of a tough, adherent pseudomembrane composed of a mixture of fibrin, dead cells, and bacteria. The membrane usually begins on the tonsils or posterior of the pharynx. In more severe cases, it spreads by progressively extending over the pharyngeal wall, fauces, and soft palate and into the larynx, which may result in respiratory obstruction. Toxin entering the blood stream causes tissue damage at distant sites, particularly the heart (myocarditis), nerves (demyelination), and kidney (tubular necrosis). Nontoxigenic strains may cause mild local respiratory disease, sometimes including a membrane.
Diphtheria toxin is an extremely potent inhibitor of protein synthesis, and the estimated human lethal dose is 0.1 mg/kg. The extent of toxin absorption varies with the site of infection, being much less from the skin or nose than from the pharynx.
Clinical Manifestations
Respiratory Diphtheria
Infection limited to the anterior nares is manifested as a chronic serosanguineous or seropurulent discharge without fever or significant toxicity. A whitish membrane may be observed on the septum. The faucial (pharyngeal) form is most common. After an incubation period of 1 to 7 days, the illness begins with a sore throat, malaise, and mild to moderate fever. Initially there is mild pharyngeal erythema, usually followed by progressive formation of a whitish tonsillar exudate, which over a period of 24 to 48 hours changes into a grayish membrane that is tightly adherent and bleeds on attempted removal. In more severe cases, the patient appears toxic and the membrane is more extensive. Cervical adenopathy and soft tissue edema may occur and result in the typical bull neck appearance and stridor. Laryngeal involvement, which may develop on its own or as a result of membrane extension from the nasopharynx, is manifested as hoarseness, stridor, and dyspnea.
The likelihood of toxic complications depends primarily on the interval between disease onset and administration of antitoxin. The severity of disease at initial evaluation closely predicts the likelihood of a severe clinical course, complications, and death. Myocarditis typically occurs in the first or second week after the onset of respiratory symptoms and develops either suddenly or insidiously with signs of low cardiac output and congestive failure. Conduction disturbances, which may occur without other signs of myocarditis, include ST-T wave abnormalities, arrhythmias, and heart block. Neurologic impairment is manifested as cranial nerve palsies and peripheral neuritis. Palatal or pharyngeal paralysis (or both) occurs during the acute phase; peripheral neuritis, symmetrical and predominantly motor, occurs 2 to 12 weeks after onset of the disease. Motor deficit may range from minor proximal weakness to complete paralysis. Complete recovery is the rule. In fulminant, sometimes called “hypertoxic,” diphtheria, toxic circulatory collapse with hemorrhagic features occurs.
Cutaneous Diphtheria
Cutaneous diphtheria lesions are classically indolent, deep, punched-out ulcers that may have a grayish-white membrane. However, the lesions may be indistinguishable from impetigo, or C. diphtheriae may infect chronic dermatoses such as stasis dermatitis. Coinfection with Streptococcus pyogenes or Staphylococcus aureus, or both, occurs frequently. Toxic complications of cutaneous diphtheria are rare.
Diagnosis
The decision to initiate therapy should be based on clinical grounds because delayed treatment, especially delays in antitoxin administration, is associated with worse outcomes. A high index of suspicion is required. Specimens for culture should be taken from beneath the membrane, from the nasopharynx, and from any suspicious skin lesions. Because special media are required, the laboratory should be alerted to the concern about diphtheria. C. diphtheriae is best isolated on selective media that inhibit the growth of other nasopharyngeal organisms; one containing potassium tellurite is generally used. Based on colonial morphology and Gram stain appearance, a presumptive diagnosis may be possible within 18 to 24 hours. Cultures may be negative if the patient previously received antibiotics. Toxigenicity testing should be performed on all C. diphtheriae isolates. Because both nontoxigenic and toxigenic strains may be isolated from the same patient, more than one colony should be tested. Traditional methods include guinea pig inoculation and the Elek test, in which the isolate and appropriate controls are streaked on a culture plate in which a filter strip soaked with antitoxin has been embedded; toxin production is confirmed by an immunoprecipitation line in the agar. Polymerase chain reaction may allow both detection of the organism and determination of toxigenicity.
Differential Diagnosis
The differential diagnosis includes streptococcal and viral tonsillopharyngitis, infectious mononucleosis, Vincent's angina, candidiasis, and acute epiglottitis. A history of travel to a region with endemic diphtheria or a history of contact with a recent immigrant from such an area increases the possibility of diphtheria, as does a pre-antitoxin treatment serum antitoxin level of less than 0.01 IU/mL.
Treatment
The goals of treatment are to neutralize the toxin rapidly, eliminate the infecting organism, provide supportive care, and prevent further transmission (Table 315-1). The mainstay of therapy is equine diphtheria antitoxin. Because only unbound toxin can be neutralized, treatment should commence as soon as the diagnosis is suspected, and each day of delay in administration increases the likelihood of a fatal outcome. A single dose ranging in quantity from 20,000 units for localized tonsillar diphtheria up to 100,000 units is given for extensive disease with severe toxicity. Antitoxin may be administered intramuscularly or intravenously; particularly for more severe cases, the intravenous route is preferred. Tests for sensitivity to antitoxin should be performed before administering it and desensitization carried out if necessary. Antibiotic therapy, by eliminating the organism, halts toxin production, limits local infection, and prevents transmission. Parenteral penicillin (4 to 6 million U/day) and erythromycin (40 mg/kg/day in four divided doses; maximum of 2 g/day, usually orally if the patient can swallow) are the drugs of choice. General supportive care includes ensuring a secure airway, electrocardiographic monitoring for evidence of myocarditis, treating heart failure and arrhythmias, and preventing secondary complications of neurologic impairment such as aspiration pneumonia. The patient should be in strict isolation until follow-up cultures are negative. Convalescing patients should receive diphtheria toxoid.
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The local health department must be notified. Close contacts should have cultures performed and be administered prophylactic antibiotics. A positive culture in a contact may confirm the diagnosis if the patient is culture negative. All contacts without full primary immunization and a booster within the preceding 5 years should receive diphtheria toxoid. Because manufacturers in the United States discontinued diphtheria antitoxin production, no licensed product is available. However, diphtheria antitoxin for the therapeutic purposes can be obtained from the Centers for Disease Control and Prevention (CDC), which distributes an European-produced antitoxin (Pasteur Merieux, Lyon, France) under an Investigational New Drug protocol.
Prevention
Immunization with diphtheria toxoid is the only effective means of primary prevention. The primary series is four doses of diphtheria toxoid (given with tetanus toxoid and pertussis vaccine) at 2, 4, 6, and 15 to 18 months; a preschool booster dose is given at 4 to 6 years of age. Thereafter, boosters should be given as part of the adolescent immunization visit (i.e., between 11 and 13 years of age), followed by doses administered every 10 years. Since 2005, the CDC recommends the routine use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine, adsorbed (Tdap), in adolescents 11 to 18 years of age in place of tetanus and diphtheria toxoid (Td) vaccines. In addition, the CDC recommends routine use of a single dose of Tdap for adults 19 to 64 years of age to replace the next booster dose of Td.
Prognosis
Diphtheria, at the beginning of the 21st century, remains a serious disease associated with a high case-fatality rate. In the United States, the diphtheria case-fatality rate has remained virtually unchanged (between 5% and 10%) over recent decades.
OTHER CORYNEBACTERIUM SPECIES
Corynebacteria other than C. diptheriae are ubiquitous in the environment and are among the normal flora colonizing humans and animals. The pathogenic potential of many of these organisms was not appreciated in the past, but many are now known to be associated with specific and often serious infectious diseases, especially in immunosuppressed, chronically ill, and hospitalized patients (Table 315-2). In general, these organisms remain susceptible to vancomycin, but resistance to other classes of antimicrobials is not uncommon and varies among species.
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