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Diphtheria

by Larry M. Bush, MD, Maria T. Perez, MD

Diphtheria is an acute pharyngeal or cutaneous infection caused mainly by toxigenic strains of Corynebacterium diphtheriae and rarely by other, less common Corynebacterium sp. Symptoms are either nonspecific skin infections or pseudomembranous pharyngitis followed by myocardial and neural tissue damage secondary to the exotoxin. An asymptomatic carrier state also exists. Diagnosis is clinical and confirmed by culture. Treatment is with antitoxin and penicillin or erythromycin. Childhood vaccination should be routine.

Corynebacterium diphtheriae usually infect the nasopharynx (respiratory diphtheria) or skin.

Diphtheria toxin

Diphtheria strains infected by a β-phage, which carries a toxin-encoding gene, produce a potent toxin. This toxin first causes inflammation and necrosis of local tissues and then can damage the heart, nerves, and sometimes the kidneys. Nontoxigenic strains of C. diphtheriae can also cause nasopharyngeal infection and sometimes systemic disease (eg, endocarditis, septic arthritis).

Epidemiology and transmission

Humans are the only known reservoir for C. diphtheriae. The organism is spread by

  • Respiratory droplets

  • Contact with nasopharyngeal secretions

  • Contact with infected skin lesions

  • Fomites (rare)

A carrier state is common in endemic regions but not in developed countries. Immunity derived from vaccination or active infection may not prevent patients from becoming carriers; however, most patients who are adequately treated do not become carriers. Patients with clinical illness or asymptomatic carriers may transmit the infection.

Poor personal and community hygiene contributes to the spread of cutaneous diphtheria. In the US, the highest incidence rates in the past were reported in states with substantial populations of Native Americans. However currently, there is no geographic concentration of cases in the US.

Diphtheria is endemic in many countries in Africa, South America, South and Southeast Asia, and the Middle East and in Haiti and the Dominican Republic (travel information about diphtheria is available at the Centers for Disease Control and Prevention [CDC] web site ). Diphtheria is now rare in developed countries because childhood immunization is widespread. However, after the breakup of the former Soviet Union, vaccination rates in its constituent countries fell, followed by a marked rise in diphtheria cases. Susceptibility has also increased because booster immunization rates in adults are declining.

Symptoms and Signs

Symptoms vary depending on where the infection is and on whether the strain produces toxin. Most respiratory infections are caused by toxigenic strains. Cutaneous infections are caused by toxigenic and nontoxigenic strains. Toxin is poorly absorbed from the skin; thus, toxin complications are rare in cutaneous diphtheria.

Pharyngeal infection

After an incubation period, which averages 5 days, and a prodromal period of between 12 and 24 h, patients develop mild sore throat, dysphagia, low-grade fever, and tachycardia. Nausea, emesis, chills, headache, and fever are more common among children.

If a toxigenic strain is involved, the characteristic membrane appears in the tonsillar area. It may initially appear as a white, glossy exudate but typically becomes dirty gray, tough, fibrinous, and adherent so that removal causes bleeding. Local edema may cause a visibly swollen neck (bull neck), hoarseness, stridor, and dyspnea. The membrane may extend to the larynx, trachea, and bronchi and may partially obstruct the airway or suddenly detach, causing complete obstruction.

Mild disease with a serosanguineous or purulent discharge and irritation of the external nares and upper lip occurs in patients who have only nasal diphtheria.

Skin infection

Skin lesions usually occur on the extremities and are varied in appearance, often indistinguishable from chronic skin conditions (eg, eczema, psoriasis, impetigo). A few patients have nonhealing, punched-out ulcers, occasionally with a grayish membrane. Pain, tenderness, erythema, and exudate are typical. If exotoxin is produced, lesions may be numb. Concomitant nasopharyngeal infection occurs in 20 to 40% by direct or indirect inoculation with the organism, often from preexisting chronic skin lesions.

Complications

The main complications are cardiac and neurologic.

Myocarditis is usually evident by the 10th to 14th day but can appear any time during the 1st to 6th wk, even while local respiratory symptoms are subsiding; risk of cardiac toxicity is related to degree of local infection. Insignificant ECG changes occur in 20 to 30% of patients, but atrioventricular dissociation, complete heart block, and ventricular arrhythmias may occur and are associated with a high mortality rate. Heart failure may develop.

Nervous system toxicity is uncommon (about 5%) and limited to patients with severe respiratory diphtheria. The toxin causes a demyelinating polyneuropathy that affects cranial and peripheral nerves. The toxic effects usually begin during the 1st wk of illness with loss of ocular accommodation and bulbar palsy, causing dysphagia and nasal regurgitation. Peripheral neuropathy appears during the 3rd to 6th wk. It is both motor and sensory, although motor symptoms predominate. Resolution occurs over many weeks.

Diagnosis

  • Gram stain and culture

Diphtheria needs to be considered in patients with nonspecific findings of pharyngitis, cervical adenopathy, and low-grade fever if they also have systemic toxicity plus hoarseness, palatal paralysis, or stridor. The appearance of the characteristic membrane suggests the diagnosis.

Gram stain of the membrane may reveal gram-positive bacilli with metachromatic (beaded) staining in typical Chinese-character configuration. Material for culture should be obtained from below the membrane, or a portion of membrane itself should be submitted. The laboratory should be notified that C. diphtheriae is suspected, so that special culture media (Loeffler or Tindale) can be used. In vitro testing for toxin production (modified Elek test) is done to differentiate toxigenic from nontoxigenic strains.

Cutaneous diphtheria should be considered when a patient develops skin lesions during an outbreak of respiratory diphtheria. Swab or biopsy specimens should be cultured. Patients with cutaneous diphtheria may be coinfected with group A streptococci or Staphylococcus aureus.

ECG should be done to look for ST-T wave changes, QTc prolongation, and/or 1st-degree heart block related to myocarditis, which often becomes evident as the respiratory symptoms resolve.

Treatment

  • Diphtheria antitoxin

  • Penicillin or erythromycin

Symptomatic patients with respiratory diphtheria should be hospitalized in an ICU to monitor for respiratory and cardiac complications. Isolation with respiratory-droplet and contact precautions is required and must continue until 2 cultures, taken 24 and 48 h after antibiotics are stopped, are negative.

Diphtheria antitoxin must be given without waiting for culture confirmation because the antitoxin neutralizes only toxin not yet bound to cells. The use of antitoxin for cutaneous disease, without evidence of respiratory disease, is of questionable value because toxic sequelae have rarely been reported in cutaneous diphtheria; however, some experts recommend it. In the US, antitoxin must be obtained from the CDC at 404-639-2889 (See also the CDC’s notice regarding availability of diphtheria antitoxin ). Caution : Diphtheria antitoxin is derived from horses; therefore, a skin (or conjunctival) test to rule out sensitivity should always precede administration (see Specific tests). The dose, ranging from 20,000 to 100,000 units IM or IV, is determined by the site and severity of symptoms, duration of the disease, and complications. If an allergic reaction occurs, 0.3 to 1 mL epinephrine 1:1000 (0.01 mL/kg) should immediately be injected sc, IM, or slowly IV. In highly sensitive patients, IV administration of antitoxin is contraindicated.

Antibiotics are required to eradicate the organism and prevent spread; they are not substitutes for antitoxin. Adults may be given either erythromycin 40 mg/kg/day (maximum, 2 g/day) po or by injection q 6 h for 14 days or procaine penicillin G IM daily (300,000 units/day for those weighing ≤ 10 kg and 600,000 units/day for those weighing > 10 kg) for 14 days. When patients are able to tolerate oral drugs, they should be switched to penicillin 250 mg po qid or erythromycin 500 mg po q 6 h for a total of 14 days treatment. Children should be given procaine penicillin G 12,500 to 25,000 units/kg IM q 12 h or erythromycin 10 to 15 mg/kg (maximum, 2 g/day) IV q 6 h, with a similar switch to oral drugs when tolerated. Vancomycin or linezolid can be used if antibiotic resistance is detected. Organism elimination should be documented by 2 consecutive negative throat and/or nasopharyngeal cultures done 1 to 2 days and 2 wk after completion of antibiotic treatment.

Vaccination is required after recovery for patients who had diphtheria because infection does not guarantee immunity.

Recovery from severe diphtheria is slow, and patients must be advised against resuming activities too soon. Even normal physical exertion may harm patients recovering from myocarditis. Overall mortality is 3%; it is higher in those with delayed presentation or myocarditis and in children < 15 yr.

For cutaneous diphtheria, thorough cleansing of the lesion with soap and water and administration of systemic antibiotics for 10 days are recommended.

Prevention

Prevention consists of infection control measures (respiratory droplet isolation until 2 cultures at least 24 h apart are negative) plus

  • Vaccination (primary and postexposure)

  • Antibiotics

Vaccination

The vaccine for diphtheria contains diphtheria toxoid; it is available only in combination with other vaccines.

Everyone should be vaccinated at prescribed intervals using diphtheria-tetanus–acellular pertussis (DTaP) vaccine for children and tetanus-diphtheria (Td) or tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) for adolescents and adults (see Diphtheria-Tetanus-Pertussis Vaccine). (See also the CDC’s National Immunization Program Childhood and Adolescent Immunization Schedule and their Adult Immunization Recommendations .)

After exposure, diphtheria immunization should be updated in all contacts (including hospital personnel) who have not completed a primary series or who have gone > 5 yr since their last booster dose. The vaccine should also be given if immunization status is unknown. An age-appropriate diphtheria toxoid-containing vaccine is used.

Postexposure antibiotics

All close contacts should be examined; surveillance for evidence of disease is maintained for 7 days. Nasopharyngeal and throat cultures for C. diphtheriae should be done regardless of immunization status.

Asymptomatic contacts should be treated with erythromycin 500 mg (10 to 15 mg/kg for children) po q 6 h for 7 days or, if adherence is uncertain, a single dose of penicillin G benzathine (600,000 units IM for patients < 30 kg and 1.2 million units IM for those > 30 kg).

If cultures are positive, an additional 10-day course of erythromycin should be given; carriers should not be given antitoxin. After 3 days of treatment, carriers can safely resume work while continuing to take antibiotics. Cultures should be repeated; 24 h after the completion of antimicrobial therapy, 2 consecutive culture sets of the nose and throat should be collected 24 h apart. If results are positive, another course of antibiotics is given and cultures are done again.

Key Points

  • Usually, diphtheria is a cutaneous or nasopharyngeal infection, but a potent toxin produced by phage-infected organisms can damage the heart, nerves, and sometimes the kidneys.

  • Diphtheria is rare in developed countries because of widespread vaccination but is endemic in many developing countries; rates are increasing slightly in developed countries because rates of vaccination and revaccination are declining.

  • Pharyngeal infection causes a characteristic membrane in the tonsillar area; it may initially appear as a white, glossy exudate but typically becomes dirty gray, tough, fibrinous, and adherent.

  • Treat with diphtheria antitoxin and penicillin or erythromycin; document cure by culture.

  • Vaccinate patients after recovery, and vaccinate close contacts who have not completed a primary series or who have gone > 5 yr since their last booster.

  • Do nasopharyngeal and throat cultures of close contacts regardless of their immunization status.

  • Give antibiotics to close contacts; duration of treatment depends on culture results.

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  • ERY-TAB, ERYTHROCIN
  • VANCOCIN
  • ADRENALIN
  • ZYVOX

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