Chapter 261. Diphtheria

Diphtheria, caused by Corynebacterium diphtheriae, occurs worldwide. Toxigenic strains produce a protein toxin that leads to the formation of pseudomembranes in the pharynx and respiratory tract, as well as systemic toxicity including myocarditis and polyneuropathy. It may present at any time of the year, although it is most common during winter. Because humans are the only significant reservoir, closeness and duration of contact with an ill person or a healthy carrier are important determinants of infection spread. As a result, attack rates in households and in crowded living conditions are high.

Epidemiology

Human nasopharyngeal carriers of C diphtheriae are the principal source of new infections, but cutaneous lesions can transmit infection as well. In temperate climates, the skin lesions of diphtheria are superficial, indolent sores that resemble impetigo. Individuals with skin lesions generally do not develop toxic manifestations. Untreated, healthy nasopharyngeal carriers can be colonized for many weeks.

The incidence of diphtheria is inversely related to the percentage of immune individuals in an area and remains a common disease in countries without effective immunization programs. The incidence of diphtheria in the United States has declined dramatically since aggressive immunization efforts were begun in 1980; in fact, less than five patients with diphtheria are reported annually. Concurrently, diphtheria has shifted from a disease of children to a disease of adults with waning immunity.1 The potential for outbreaks continues, however, if segments of a community are not immunized.

C diphtheriae is comprised of irregularly staining gram-positive, nonspore-forming, unencapsulated slender rods. Branching and clubbed ends result in a cuneiform appearance. Metachromatic granules are common. There are three phenotypes of the organism: gravis, intermedius, and mitis, differentiated by colony morphology, growth characteristics, and biochemical reactions. All are capable of elaborating a cytotoxic exotoxin, which interferes with protein synthesis in host cells. The ability of a strain of C diphtheriae to produce toxin is conferred by a lysogenic bacteriophage that carries the gene for toxin production. The clinical signs and symptoms depend on the primary site of infection. Toxins produced by the three types are qualitatively similar, but the gravis and intermedius strains produce more toxin than does the mitis strain.

Clinical Manifestations

Diphtheria presents with respiratory infection that can cause respiratory obstruction, or with infected skin lesions that lack a characteristic appearance. With either presentation, toxin produced by the organism results in further symptoms.

Respiratory Diphtheria

This usually has an insidious onset with symptoms of a mild sore throat with slight redness and low-grade fever. Systemic signs of illness are absent in the early stages. Within 1 or 2 days, areas of yellow or “dirty” white exudate appear, most frequently on or adjacent to the tonsils; these areas subsequently coalesce to form a light reflective, sharply outlined pseudomembrane on the mucous membranes of the pharynx, tonsils, and uvula. Pseudomembranes consist of necrotic epithelium embedded in an inflammatory, organized exudate at the surface. Less frequently, such lesions are found in the nose, larynx, and lower respiratory tract. Rarely, pseudomembranous lesions extend to the middle ear, the esophagus or the stomach, or involve the skin or mucosa of the genitalia. Inflammatory changes in underlying epithelium may extend into the submucosa, where hemorrhage may be present. The bacilli remain in these surface lesions and rarely invade deeper structures or cause bacteremia. Diphtheria toxin is absorbed from the local lesion, causing damage in distant organs and tissues.

Persons with partial antitoxic immunity may not progress beyond the exudative stage. In those lacking immunity, the pseudomembrane may spread to the soft palate and to the posterior pharynx, but not anteriorly. There is bleeding with attempts to remove the pseudomembrane. Cervical lymph nodes may be mildly enlarged, but the single large, anterior cervical nodes characteristic of streptococcal infection are not found. With extensive membrane formation, there may be dysphagia and drooling. After approximately 5 days, the pseudomembrane changes to a grayish color secondary to hemorrhage as it loosens and sloughs. In approximately 10% of patients, the illness has a hyperacute presentation with high fever, systemic toxicity, cerebral obtundation, and rapid proliferation of the pseudomembrane associated with marked edema of the face and neck, a phenomenon referred to as “bull neck” diphtheria, which has a grave prognosis.

In less than 5% of patients, diphtheria of the laryngotracheal area occurs in the absence of tonsillopharyngeal involvement, but in about 10% of patients, there is secondary downward spread from the pharynx. Varying degrees of hoarseness, stridor, and respiratory embarrassment occur, depending on the extent and thickness of the membrane in relation to the caliber of the airway. Young children are at higher risk of compromise because of small airways. Rarely, the membrane extends into the bronchi, resulting in a virtual cast of the airway, which is invariably fatal.

Primary nasal diphtheria is more common in infants and young children. The discharge is mucoid, profuse, and grayish in color. After a few days when the membrane begins sloughing, there is often blood in the discharge. This is the mildest form of diphtheria and seldom has toxic manifestations.

Skin and Mucous Membranes

Rarely, the primary site of infection is the mucous membrane of the eye, vagina, or ear. An ulcerating lesion with exudate or pseudomembrane forms, but these self-limited lesions are only rarely associated with toxicity. Skin lesions are most often superficial, have no characteristic appearance, and are not associated with pseudomembranes. Occasionally, ulcerating or ecthymatous lesions develop. They occur in persons with preexisting antitoxic immunity, or they induce immunity because they are not associated with toxic manifestations. Individual lesions heal, but new ones may form at the sites of breaks in the integrity of skin from insect bites or trauma over a period of weeks.

Effects of Toxin

The heart, kidneys, and neural system are susceptible to damage by diphtheria toxin. The degree of toxic damage is determined by two factors: (1) the extent of disease at the primary site and, hence, the amount of toxin produced and disseminated hematogenously; and (2) the amount of circulating antitoxin. The latter is determined by both the preexisting antitoxin resulting from prior subclinical infection or immunization and by the therapeutic amounts of antitoxin administered. Because immunity wanes with the passing years, previously immunized persons can eventually become susceptible to toxin. Electrocardiographic evidence of myocardial toxicity is present in many patients with diphtheria, but clinical myocarditis develops in about 10% of patients. Myocarditis generally develops during the first week of illness, but onset can be delayed for 1 month or longer. Dysrhythmias are common. Death occurs more often from severe dysrhythmia (including complete heart block) than from heart failure. On histology, myocarditis is characterized by degenerative or “toxic” damage, rather than by inflammation. Minute hemorrhages may be present, or, in some areas, an accompanying round-cell infiltration may be seen. The conducting system is frequently involved.

Renal failure is rare, but minor injury as reflected by changes in the urinalysis (proteinuria, cylindruria, increased cells) is common. If toxic nephropathy develops, it is almost uniformly fatal. Hemolytic uremic syndrome has been reported in diphtheria. The kidneys may exhibit cloudy swelling, with swollen granular epithelial cells of the convoluted tubules. Interstitial nephritis may occur. Lesions in the adrenal cortex, similar to those present in meningococcemia, are often found in fatal infections. Hepatic function may be mildly impaired; liver cells show degenerative changes at autopsy, with scattered areas of focal necrosis.

Neural involvement occurs in 5% to 10% of patients, and can be manifested as isolated peripheral nerve palsies or as a symptom complex mimicking Guillain-Barré syndrome. Contiguous muscles in the palate, pharynx, or larynx are most commonly involved and tend to be affected earlier in the disease course than the extraocular muscles, diaphragm, or muscles supplied by peripheral nerves. Paralysis can occur as early as the first week of illness, but more often develops between the second and sixth week after onset of the respiratory illness. If the patient does not succumb to respiratory complications of paralysis, full recovery can be expected within a few weeks. Degenerative changes in the nervous system occur in nearly all fatal infections. In the spinal cord, changes are seen in the ganglion cells of the anterior horns and in the posterior root ganglia. The cranial nerves and their centers can be affected, but the cortex is spared. Other lesions encountered are degenerative changes in the spleen and lymph nodes; occasionally, subcapsular hemorrhages in these organs are seen. Subcutaneous hemorrhages are frequent.

Diagnosis

Many bacterial and viral pathogens can cause pseudomembranous tonsillitis, the most common being Streptococcus pyogenes, adenoviruses, and Epstein-Barr virus. Although there is sometimes exudate on the part of the uvula touching the enlarged tonsil in these conditions, the pseudomembrane does not otherwise extend away from the tonsil. In rare instances of laryngeal diphtheria without oropharyngeal involvement, the diagnosis is suspected if there is a history of exposure to diphtheria or when a pseudomembrane is seen at the time of laryngoscopy or bronchoscopy. Otherwise, the differential diagnosis from viral causes of croup is exceedingly difficult.

When diphtheria is suspected, attempts should be made to isolate the organism from the local lesion. It is advisable to take specimens for culture from the nasopharynx as well as the throat because the yield of positive results is 20% greater with two cultures as opposed to one culture. If transport time to the laboratory is longer than 24 hours, the swabs should be placed in a laboratory-recommended commercial transport medium. Specimens should be inoculated onto recommended media (usually a Loeffler or Pai slant, a cystine-tellurite agar plate, and a 5% sheep’s blood agar plate) and incubated overnight at 35°C (95°F). Growth from slants may be stained with Neisser or Loeffler methylene blue and examined for the characteristic morphologic appearance of C diphtheriae (eg, metachromatic granules). Toxigenicity is usually determined using the modified Elek immunodiffusion test in reference or state laboratories.

The degree of leukocytosis in the peripheral blood generally reflects the severity of disease. In mild to moderate disease, the leukocyte count is between 10,000 and 20,000/μL. The likelihood of a fatal outcome rises sharply in patients with leukocyte counts higher than 25,000/μL. Thrombocytopenia and disseminated intravascular coagulation (DIC) are rare. Some patients develop mild anemia.

In postdiphtheritic paralysis, protein concentrations increase in the cerebrospinal fluid (CSF), but there is no increase in the number of cells and the glucose content is normal, as occurs in idiopathic Guillain-Barré syndrome. The protein content continues to increase during the initial weeks of neurologic symptoms and slowly returns to normal after clinical recovery.

Albuminuria is common, and in severe disease, there may be cells and casts in the urine.

Treatment

Diphtheria antitoxin neutralizes circulating toxin but has no effect on toxin that is bound to cells. It should be administered as soon as possible after onset of disease. Therefore, the decision to treat is usually made before culture results are available and is based on a compatible clinical picture in a susceptible individual. Diphtheria antitoxin is an equine serum, so tests for sensitivity must be done by instilling a 1:10 dilution into the conjunctival sac or by performing an intradermal test dose with a 1:100 dilution of the antiserum. If the patient has an immediate reaction, a desensitization procedure is done. Details of appropriate sensitivity testing and interpretations of results are usually provided with antitoxin available from the Centers for Disease Control and Prevention.

The dosage of antitoxin is empirical and based on the extent of disease. Dosage is not based on body weight, but on the estimated amount of toxin present. Suggested dosages are presented in eTable 261.1. The antiserum is administered intravenously. Antitoxin is of dubious value for patients with cutaneous diphtheria, but some authorities recommend it because toxic manifestations have occasionally been reported.

Antibiotic therapy has little or no effect on the clinical evolution of diphtheria. It is given primarily to render the patient noncontagious. C diphtheriae is susceptible to penicillin and erythromycin, and probably to other macrolides (eg, clarithromycin, azithromycin) as well. Erythromycin (40 mg/kg/d divided every 6 hours) is given by mouth. Effective dosage and duration of the newer macrolides have not been defined, nor have these drugs been evaluated in clinical cases or in carriers. Alternatively, daily procaine penicillin G (25,000–50,000 U/kg in two divided doses) can be given intramuscularly, or aqueous crystalline penicillin G (100,000–150,000 U/kg divided in four doses) can be given to the patient. Treatment is given for 14 days. After completion of antibiotic therapy, the throat and nasopharynx should be cultured three times, at least 24 hours apart, to determine whether the pathogen has been eradicated. Respiratory isolation precautions are maintained until there is culture confirmation of eradication of the pathogen from the nasopharynx. Some patients with cutaneous diphtheria have asymptomatic respiratory tract colonization with C diphtheriae, and thus, throat and nasopharyngeal cultures are necessary in these patients as well.2 If there is persistent nasopharyngeal carriage after the first course of therapy, a repeat course of erythromycin therapy should be given.

Corticosteroid therapy (to mitigate myocarditis or nephritis) is ineffective and is not recommended.3 Carnitine is a cofactor in the transport of fatty acids to the interior of cell mitochondria. Because fatty acids accumulate in the cytoplasm of human heart cells in patients with diphtheritic myocarditis, carnitine might be beneficial. In one study, 10% DL-carnitine (100 mg/kg/d in two divided doses for 4 days) decreased the incidence of myocarditis as compared with a control group, but this needs to be confirmed before carnitine can be recommended as routine therapy.4 Treatment is otherwise supportive.

A patent airway must be maintained in patients with diphtheria. Nasotracheal intubation or tracheostomy may be needed. Patients should be monitored carefully for signs or symptoms of myocarditis, nephropathy, or neuropathy. Patients should be observed closely for signs of laryngeal, pharyngeal, or diaphragmatic paralysis. If there is difficulty with swallowing, oral feedings should be withheld and parenteral nutrition provided. Respiratory paralysis is managed by standard procedures. During the stage of sloughing of the pseudomembrane, tracheal suction may be successful in removing obstructive fragments.

Exposed household and other close contacts of an index patient with diphtheria are at increased risk of becoming asymptomatic carriers or of developing disease. Immunization provides antitoxic immunity, but no immunity to infection with C diphtheriae. All exposed persons should be examined promptly. Individuals with symptoms consistent with diphtheria should be investigated and treated appropriately. Cultures should be obtained from all exposed, asymptomatic persons, and they should be considered potentially contagious until the culture results are known. All close contact should be kept under surveillance for 7 days.

Previously immunized contacts should be given a booster dose of diphtheria toxoid if they have not received a booster within 5 years. Individuals who are not immunized, or whose immunization status is uncertain, should be given prophylaxis with erythromycin (40 mg/kg/d in four divided doses for 7 days) or a single intramuscular injection of 50,000 U benzathine penicillin G per kilogram (maximum 1,200,000 U). Immunization with DtaP, Td, or Tdap, depending on age, should be initiated. If the individual cannot be kept under surveillance, some authorities recommend giving 5000 to 10,000 U of diphtheria antitoxin intramuscularly. In most circumstances, the risk of allergic reactions makes this practice inadvisable.

Prognosis

Overall, the fatality rate is about 10%, but the prognosis depends on type of disease, age, and general condition of the patient, and the interval from onset of disease to receipt of antitoxin therapy. More than half the patients with bull neck diphtheria die despite aggressive intensive care. If myocarditis or renal failure occurs early in the course of disease, the prognosis is grim. If the patient is managed in an intensive care facility, death from airway obstruction is unlikely, unless pseudomembrane extends into the bronchi. After recovering from the acute illness, patients remain at risk for late development of paralysis or myocarditis. There are no permanent sequelae of diphtheria unless anoxic damage has occurred.

Prevention

Because an attack of diphtheria does not provide reliable immunity to the toxin, recovered patients should receive diphtheria toxoid. Immunity is associated with a level of specific antibodies of 0.01 IU/mL. Newborn infants have transient immunity from maternal antibodies when the mother is immune. Immunization recommendations are found in Chapter 244.