Pediatrics

Diphtheria

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Diphtheria? What are the typical findings for this disease?

Diphtheria is an infection caused by toxigenic strains of Corynebacterium diphtheriae, an anaerobic, pleomorphic Gram positive bacillus. Infection usually involves the throat, but the nasal mucosa and/or larynx may be affected. Initial symptoms include sore throat and, in some cases, low grade fever. These mild complaints are followed after 2-4 days by pseudomembrane formation on the pharyngeal walls, tonsils, uvula, and soft palate. The membrane may extend to the larynx and trachea. The soft tissue of the neck becomes edematous, and enlarged lymph nodes cause swelling of the neck - the so-called "bull neck" appearance.

Patients with diphtheria may hold the neck in extension to relieve pressure on the throat and larynx. The definition of the angle of the jaw and sternocleidomastoid muscle is "erased" by the brawny edema that is pitting, warm, tender, but not erythematous. Swallowing may be compromised by unilateral or bilateral paralysis of the muscles of the palate.

In untreated patients complications include extension of the pseudomembrane leading to airway compromise. Circulating toxin can precipitate circulatory collapse, respiratory failure, stupor, coma, and death. Diphtheria toxin may affect the myocardium and central nervous system, even in patients whose pharyngeal involvement was mild.

Nasal diphtheria, more common in infants, is less likely to lead to serious systemic disease, because the toxin is less well-absorbed from the nasal mucosa. In this condition, initial clear nasal discharge is followed by serosanguineous, and then mucopurulent drainage with excoriation of the upper lip and nares. Pseudomembrane may develop on the nasal septum, and a foul odor may be appreciated.

Cutaneous diphtheria results in pain, tenderness, and erythema at the site of infection, leading to ulceration and formation of a brownish-gray membrane. This manifestation is more common in tropical regions.

Unusual manifestations of diphtheria

Unusual sites of infection with toxigenic C. diphtheriae include the external ear, the palpebral conjunctivae, and the genital mucosa. Rarely, bacterial endocarditis due to non-toxigenic strains has been reported. Sporadic case of C. diphtheriae bacterema have been reported rarely, but they have been universally fatal.

What other disease/condition shares some of these symptoms?

The clinical findings of pharyngeal diphtheria are distinct from those of other infectious causes of oropharyngeal disease. The leather-like pseudomembrane extending beyond the tonsillar area, along with a paucity of systemic signs and symptoms, including low or non-existent fever, help distinguish pharyngeal diphtheria from other causes of exudative pharyngitis, such as Streptococcus pyogenes, adenovirus, and Epstein-Barr virus.

The lack of oropharyngeal ulceration distinguishes diphtheria from herpes simplex infection or hand-foot-mouth disease caused by enteroviruses. Oropharyngeal candidiasis and mucositis may be associated with similar physical findings to early diphtheria, but the clinical circumstances should prevent confusion. The neck involvement of phlebitis and thrombosis of the jugular veins (Lemierre disease) is unilateral, and no pseudomembrane is seen in the oropharynx of these patients.

If a lumbar puncture is performed in a patient with neurologic complications, elevated CSF protein may lead to an erroneous diagnosis of Guillain-Barre syndrome.

What caused this disease to develop at this time?

C. diptheriae is spread by respiratory tract droplets and by contact with exudate from skin lesions. Untreated, infected individuals shed the organism from the nose and throat or from skin lesions for 2-6 weeks following infection. Rarely, the organism may be acquired by contact with contaminated dust, food, or fomites. The incubation period is usually 2-7 days, but it can be longer.

Infection due to C. diphtheriae is seen worldwide, but the incidence is higher in temperate climates and among individuals living in crowded, socioeconomically deprived conditions and in regions with low rates of immunization. Humans are the sole reservoir for this organism.

Historically, diphtheria occurred most often in children under 15 years, usually in unimmunized individuals. The disease is now rare in countries in which immunization is universal or nearly universal, but the few cases that do occur in those countries are more likely now to be in adults whose antibody against diphtheria toxin has waned. There has been no confirmed case of respiratory tract diphtheria in the United States since 2003. It is estimated that epidemic spread of toxigenic C. diphtheria can be prevented if 70%-80% of a population has been immunized.

Cutaneous diphtheria has been reported among homeless individuals living in crowded and poor hygienic conditions in the United States. When untreated, cutaneous infection is associated with prolonged shedding, environmental contamination, and transmission to close contacts.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Specimens for culture should be obtained from the nose and throat and from any mucocutaneous site suspected of being involved. In addition to exudate or secretions, a portion of the membrane should be submitted for culture. The receiving laboratory should be notified that infection with C. diphtheriae is suspected, because specific selective media will be required. Specimens to be sent to a remote laboratory should be transported in a silica gel pack or transport medium. Gram stain and fluorescent antibody staining for identification of C. diphtheriae is unreliable. Suspicious isolates should be tested for toxin production by a laboratory recommended by health department authorities.

The Shick test, which involves intracutaneous injection of diphtheria toxin, was used in the past to determine immunity to the toxin, but this test is not useful for diagnosis.

Though coryneform bacteria are frequent contaminants of blood cultures, any such bacteria isolated from a sterile site or from mucocutaneous samples from patients with suggestive disease should be identified to the species level with appropriate tests for toxin production for any C. diphtheriae isolated.

Other commonly obtained laboratory tests are not likely to be helpful in diagnosing diphtheria. The WBC count may be normal or slightly elevated. If neurologic involvement is suspected and CSF is obtained, the CSF protein may be elevated, and there may be a slight CSF pleocytosis.

If cardiac involvement is suspected an electrocardiogram may demonstrate prolonged P-R interval, ST-segment elevation, and T-wave changes. Arrhythmias may also be detected. An echocardiogram may demonstrate dilated or hypertrophic cardiomyopathy. Elevation of serum aspartate aminotransferase suggests cardiac myonecrosis.

Would imaging studies be helpful? If so, which ones?

Chest x-ray in patients with suspected cardiac involvement may demonstrate cardiac enlargement or evidence of pulmonary edema.

If you are able to confirm that the patient has diphtheria, what treatment should be initiated?

Treatment of diphtheria involves BOTH administration of equine antitoxin AND antimicrobial therapy.

Antitoxin

A single dose of antitoxin should be administered as soon as possible if the clinical condition is suggestive of diphtheria. Mortality can be reduced to less than 1% if antitoxin is administered in the first day of disease compared to 20% if administration is delayed to the 4th day. In the United States, diphtheria antitoxin can be obtained from the Centers for Disease Control and Prevention. U.S. physicians caring for patients with suspected respiratory diphtheria can obtain diphtheria antitoxin by contacting the Emergency Operations Center at 770-488-7100.

The purpose of the antitoxin is to neutralize circulating toxin; intravenous administration is preferred. Only horse antidiphtheria antiserum is available in the United States, and approximately 10% of individuals have preexisting hypersensitivity to horse serum. Approximately 8% will develop serum sickness with its administration. For this reason, a scratch test using a 1:1000 dilution of antitoxin in saline solution should be performed prior to antitoxin administration. If no reaction is seen, the scratch test should be followed by an intradermal test using a dose of 0.02 mL of a 1:1000 dilution in preservative-free isotonic saline. Even if both tests yield no reaction hypersensitivity may manifest during administration of serum, so antitoxin should be administered cautiously.

Approximately 5%-20% of individuals will manifest hypersensitivity or develop serum sickness when exposed to horse serum. The likelihood of reaction is increased in patients with a history of allergic disease or past exposure to animal serum. If hypersensitivity is suspected based on the results of the prick test or the intradermal test or based on the patient's history, desensitization must be attempted using increasing amounts and decreasing dilutions of intravenously administered antiserum at 15 minute intervals, beginning with 0.1 mL of a 1:1000 dilution and increasing to 1.0 mL of undiluted serum. Despite these precautions anaphylaxis can occur, and appropriate resources should be available to treat this complication.

The dose of intravenous antitoxin to be administered depends upon the degree and duration of illness. The recommended dose for pharyngeal/laryngeal disease of ≤ 48 hours duration is 20,000-40,000 units; for nasopharyngeal disease, 40,000-60,000 units; for extensive disease of ≥ 3 days duration or for diffuse swelling of the neck, 80,000-100,000 units. Antitoxin is probably not effective or needed for treating cutaneous disease, but some experts recommend administration of 20,000-40,000 units for this condition.

Antimicrobial therapy

Antibiotic therapy should be given along with antiserum to eradicate the organism and halt toxin production. Either erythromycin (40 to 50 mg/kg/day to a maximum of 2 grams/day orally or parenterally) for 14 days or penicillin (penicillin G, 100,000 to 150,000 U/kg/day intravenously in 4 divided doses or procaine penicillin, 25,000 to 50,000 U/kg/day IM to a maximum of 1.2 million units in two divided doses) for 14 days may be used. Other antibiotics may be effective, but their use has not been studied or approved for this purpose.

Patients with respiratory diphtheria should be isolated and placed on droplet precautions until two cultures from the nose and throat taken 24 hours after antimicrobial therapy had been completed are negative. Patients with cutaneous diphtheria should be on contact precautions until 2 cultures from the affected skin taken 24 hours after completion of antibiotics are negative.

Active immunization with diphtheria toxoid should be undertaken during convalescence, since disease does not necessarily confer immunity.

Public health officials should be notified of suspected cases of diphtheria. In addition, nasal and pharyngeal swab cultures should be obtained from all close contacts, regardless of immunization status to identify asymptomatic carriers. All household contacts and others with habitual, close contact with the patient should be treated with oral erythromycin (40-50 mg/kg/day to a maximum of 2 g/day for 7 days or with a single intramuscular dose of benzathine penicillin G (600,000 units for those weighing < 30 kg or 1.2 million units for larger children and adults).

Contacts who are found to be asymptomatic carriers should be isolated until at least two cultures taken at a minimum of 24 hours following completion of antibiotic therapy are negative. Finally, repeat cultures should be obtained 2 weeks following completion of therapy from contacts whose initial culture was positive. If these cultures are positive, the antibiotic course should be repeated. Antitoxin administration is not needed for asymptomatic carriers. Immunization should be undertaken or completed for contacts who have not been fully immunized against C. diphtheriae.

What are the adverse effects associated with each treatment option?

Administration of equine antitoxin may result in acute febrile reactions, serum sickness, or anaphylaxis. Approximately 8% of patients will develop serum sickness, and 10% have pre-existing hypersensitivity to horse serum.

Administration of erythromycin results in gastrointestinal complaints in some patients. Since erythromycin is metabolized via hepatic cytochrome P-450 enzymes, antibiotic-drug interactions can occur. Allergic reactions, including rash, fever, and anaphylaxis can occur with administration of penicillin.

What are the possible outcomes of diphtheria?

Death due to mechanical airway obstruction or to cardiac involvement occurs in at least 10% of patients with respiratory diphtheria. The prognosis depends on the immunization status of the patient, the site of involvement, and the speed with which antitoxin is administered. Patients treated on the first day of illness have a mortality rate of approximately 1%, while patients for whom antitoxin treatment is delayed as long as 4 days have a 20% risk of death.

Patients who develop cardiac involvement but who survive generally recover normal cardiac function unless toxic damages has led to a permanent arrhythmia. Recovery from neurologic complications usually is complete in surviving patients.

What causes this disease and how frequent is it?

Corynebacterium diphtheriae is an aerobic, nonencapsulated Gram positive nonmotile pleomorphic rod which has worldwide distribution. Humans are the only known reservoir. The organism can be grown on a variety of selective media, including tellurite agar or specially enriched Loffler, Pai, or Tinsdale medium. There are three phenotypes of C. diphtheriae (mitis, intermedius, and gravis), each capable of producing toxin and disease, but distinguishable from each other by growth characteristics in vitro.

The exotoxin that produces multiple complications in infected individuals is not essential for bacterial growth. It is produced only in C. diphtheriae that are lysogenic for a phage carrying the gene for toxin production.

Prior to availability and use of diphtheria toxoid to prevent disease, approximately 125,000 cases were reported in the United States annually, with approximately 13,000-15,000 deaths per year. Disease predominantly affected children under 15 years of age. The frequency of disease fell sharply after availability of vaccine. Since 1980 the incidence in the United States has been approximately 0.001 cases per 100,000 population, and there has not been a case of respiratory diphtheria reported in the United States since 2003. When immunization rates fall, as they did, for instance in the countries of the former Soviet Union during the 1990's, outbreaks can still occur.

How do these pathogens/genes/exposures cause the disease?

C. diphtheriae can cause infection of the mucosal surfaces of the upper respiratory tract and of the skin. If the infecting organism is lysogenized by the toxin-producing bacteriophage, toxin is elaborated and released after an incubation period of 2-5 days. The B fragment of the toxin attaches to host cell receptors, allowing entry into the cell. The A fragment interrupts cellular protein synthesis. The effect of toxin activity is to produce necrosis, edema, and membrane formation. The gray-black membrane is made up of epithelial cells, fibrin, inflammatory cells, erythrocytes, and organisms.

Toxin is also distributed through the blood stream and lymphatics, reaching distant organs. The heart may suffer from development of cellular infiltrate with fatty accumulation, particularly affecting the conduction system. Myelin sheaths of the nervous system undergo fatty degeneration leading to local (pharyngeal and palatal) paralysis and also affecting more distal nerves, including the muscles of respiration. Necrosis of renal tubules and hepatic parenchyma, as well as amegakaryocytic thrombocytopenia and adrenal hemorrhage may also occur.

Though antitoxin administration leads to neutralization of circulating toxin, it has no effect on toxin that has already entered cells. For this reason antitoxin should be given as quickly as possible.

What complications might you expect from the disease or treatment of the disease?

Complications of diphtheria include airway obstruction by the diphtheritic membrane and through peripharyngeal edema.

Cardiac complications, including dysrhythmias (first-, second-, and third-degree heart block, atrioventricular dissociation, ventricular tachycardia) and congestive heart failure occur in 10-25% of patients and are thought to be responsible for 50-60% of deaths due to diphtheria. Cardiac involvement may become apparent during the first 10 days of illness, or it may be delayed by several weeks, when the pharyngeal involvement is subsiding. Tachycardia out of proportion to fever is suggestive of cardiac involvement or autonomic dysfunction.

Demyelination of nervous tissue may lead to paralysis of the muscles of the soft palate and hypopharynx, and can also involve other cranial nerves. This complication may be seen as early as 10 days into the illness, but may be delayed as long as 7 weeks. Diffuse, usually bilateral involvement of the anterior horn cells of the spinal cord may cause progressive weakness, and involvement of the phrenic nerve can lead to diaphragmatic paralysis. These motor deficits may be delayed in their appearance by as long as 3 months.

How can diphtheria be prevented?

Immunization with a diphtheria toxoid-containing vaccine is effective in preventing disease. In the United States vaccine is recommended to be given using vaccine also containing tetanus toxoid and pertussis antigen at 2, 4, and 6 months of age, followed by booster doses at 12-18 months, 4-6 years, and in early adolescence.

Because of a higher likelihood of adverse reactions, children over 6 years of age should receive a reduced dose of diphtheria toxoid (2 limit of flocculation, Lf units). This dose should be repeated every 10 years throughout life. Though circulation of toxigenic strains of C. diphtheriae is low in countries where immunization is routinely used, subgroups of underimmunized individuals would be at risk of disease if exposed. A serum concentration of 0.01 to 0.1 IU/mL of antibody against diphtheria toxin is considered protective.

Public health officials should be notified of suspected cases of diphtheria. In addition, nasal and pharyngeal swab cultures should be obtained from all close contacts, regardless of immunization status to identify asymptomatic carriers. All household contacts and others with habitual, close contact with the patient should be treated with oral erythromycin (40-50 mg/kg/day to a maximum of 2 g/day for 7 days) or with a single intramuscular dose of benzathine penicillin G (600,000 units for those weighing < 30 kg or 1.2 million units for larger children and adults).

Contacts who are found to be asymptomatic carriers should be isolated until at least two cultures taken at a minimum of 24 hours following completion of antibiotic therapy are negative. Finally, repeat cultures should be obtained 2 weeks following completion of therapy from contacts whose initial culture was positive. If these cultures are positive, the antibiotic course should be repeated. Antitoxin administration is not needed for asymptomatic carriers. Immunization should be undertaken or completed for contacts who have not been fully immunized against C. diphtheriae.

What is the evidence?

Pickering, LK, Baker, CJ, Kimberlin, DW, Long, SS. "Red Book: 2009, Report of the Committee on Infectious Diseases". American Academy of Pediatrics. 2009. pp. p 280.

(This is the "go-to" resource for management of infectious diseases in children.)

Farizo, KM, Strebel, PM, Chen, RT. "Fatal respiratory disease due to Corynebacterium diphtheriae: case report and review of guidelines for management, investigation, and control". Clin Infect Dis. vol. 16. 1993. pp. 59.

Hodes, HL. "Diphtheria". Pediatr Clin North Am. vol. 26. 1979. pp. 445.

(This is an authoritative review by a giant in the field of pediatric infectious diseases.)

McMillan, JA, Feigin, R, McMillan, JA, Feigin, RD, DeAngelis, CA, Jones, MD. "Oski's Pediatrics: Principles and Practice". Lippincott Williams & Williams. 2006. pp. 1059.

(This chapter provides a comprehensive review of the disease and its management.)
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