AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The name diphtheria is derived from the Greek root for leather, which is descriptive for the pharyngeal membrane that characterizes the disease. Although its symptoms have been discussed by many authors of ancient and modern times, diphtheria has been known by its present name only since Bretonneau published a treatise in 1823. Hippocrates clinically described it, and, in the 20th century, diphtheria evolved from a major public health problem to a medical curiosity within the developed nations through the use of immunization measures.

Conjunctivitis diphtheritica has the property of exciting profuse exudation in the tissue of the conjunctivae, which has a great tendency to coagulate, leading to necrosis of the infiltrated tissue.

Pathophysiology

Diphtheria is an acute infectious disease caused by the gram-positive bacillus Corynebacterium diphtheriae. It is characterized by a primary lesion, usually within the respiratory tract, and more generalized symptoms caused by release and spread of bacterial exotoxins throughout the body. Diphtheria most commonly affects children younger than 10 years. Humans are the only known reservoir for C diphtheriae. The primary modes of spread are via airborne droplets or contact with respiratory secretions or exudates from infected skin lesions. Fortunately, the widespread immunization of infants using diphtheria toxoid has made this infection extremely rare in developed nations. Diphtheria was the leading cause of death in Canadian children aged 2-14 years only 75 years ago.

The primary pathological lesion of diphtheria is the development of a thick leathery membrane consisting of bacteria, dead cells from the mucous membranes, and fibrin. This membrane, surrounded by a narrow zone of inflammation, firmly adheres to the underlying tissues. Removal of this membrane reveals a bleeding edematous submucosal tissue. The membrane may be localized or extend widely, forming a cast of the pharynx and the tracheobronchial tree. Soft tissue edema of the airways can compromise respiratory function, and death by suffocation from soft tissue edema and aspiration of the membrane is common.

The major virulence of C diphtheriae results from the action of its potent exotoxin, a polypeptide chain produced at the site of the local lesion that passes into the bloodstream. The toxin, which inhibits protein synthesis in mammalian cells, affects all cells in the body but most prominently the heart, producing myocarditis; the kidney, resulting in renal tubular necrosis; and the nervous system, resulting in demyelination. Toxic demyelination occurs in 10% of all infected patients. The neuropathy usually occurs 2-6 weeks after infection, but it may be delayed for up to 3 months after primary infection.

Frequency

United States

At the turn of the century, in the United States, diphtheria was common, occurring primarily in children, and it was one of the leading causes of death in infants and children. In the 1920s, when data were first gathered, in the United States, there were approximately 150,000 cases and 13,000 deaths reported annually. After diphtheria immunization was introduced, the number of cases gradually fell to about 19,000 in 1945. When diphtheria immunization became widespread in the late 1940s, a more rapid decrease in the number of cases and deaths occurred.

From 1970-1979, an average of 196 cases per year were reported. Seventeen outbreaks of 15 or more cases occurred in the United States from 1959-1980, but there have been no outbreaks of multiple cases since 1980. From 1980-1989, the number of cases in the United States dropped to 24; 2 cases were fatal, and 18 occurred in persons aged 20 years or older. From 1990-2000, there were an additional 28 cases reported.  Most cases have occurred in nonimmunized (or inadequately immunized) individuals.

Since 2000, 5 or fewer cases have been reported annually in the United States.

International

The disease remains endemic in many parts of the third world, although decreases in incidence have occurred worldwide.

Epidemic diphtheria reemerged in the New Independent States (NIS) of the former Soviet Union, beginning in the Russian Federation in 1990 and affecting all 15 NIS by the end of 1994.  Approximately 90% of all diphtheria cases reported worldwide during 1990-1995 were reported from the NIS.  From 1990-1995, approximately 125,000 cases of diphtheria and 4000 deaths related to the disease were reported in the NIS. 

At the time of the disintegration of the former Soviet Union in 1991, all NIS relied on supplies of vaccine and antitoxin from Russia, and most lacked the financial resources to procure them from the international market. Mass vaccination campaigns began in 1994, and they have been successful in controlling this epidemic.

Mortality/Morbidity

The potent exotoxin can cause myocarditis, renal tubular necrosis, or toxin demyelination of the central nervous system.

Age

Children younger than 10 years more commonly are affected. 

The epidemic in the New Independent States of the former Soviet Union in 1990-1995 was characterized by a high proportion of cases among adults.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Diphtheria begins as a respiratory infection with strident coughing and fever.

Physical

• Ocular manifestations of diphtheria, as those involving other organ systems, are both a result of the primary infection (keratoconjunctivitis) and the release of exotoxin (motility disorders).
• • In the eye, conjunctival infection may be mild, resembling a viral conjunctivitis with preauricular adenopathy, palpebral and bulbar conjunctival erythema and edema, and a moderate amount of yellowish discharge.
  • The more typical diphtheric infection is that of membranous conjunctivitis. Infiltration of the conjunctival surface leads to extreme edema and erythema of the eyelids with increasing stiffness of the lids. Membrane formation occurs over the palpebral and bulbar conjunctivae, and the membrane ultimately becomes necrotic and sloughs off, leaving behind severe conjunctival scarring with formation of symblepharon, entropion, trichiasis, and tear production disturbances. The conjunctiva may become necrotic, and thrombosis of perilimbal vessels can lead to corneal ulceration and scarring and to corneal perforation from corneal ischemia.
• Up to 25% of patients with severe primary disease develop neurotoxicity from the effects of the exotoxin. Local paralysis of the soft palate and posterior pharyngeal wall are most common with other cranial neuropathies, leading to oculomotor and ciliary paralysis and facial and laryngeal weakness. Peripheral neuropathy may occur 10 days to 3 months postinfection, with proximal motor neuropathy initially, then moving distally, commonly involving dorsiflexors of the foot.
• Oculomotor palsy and abducens palsies may be unilateral, bilateral, complete, or incomplete. Facial nerve paralysis may cause difficulties with eyelid closure. Paralysis of accommodation is common, occurring in approximately 10% of patients with diphtheria. Pupillary reactions remain normal. Usually, resolution of these cranial neuropathies occurs spontaneously within 2-6 weeks.

Causes

Diphtheria is an acute infectious disease caused by the gram-positive bacillus C diphtheriae.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Gram and Wright stains of the conjunctival secretions should be obtained.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Treatment includes supportive care and isolation, as well as penicillin or erythromycin, which are extremely effective against C diphtheriae.

Diphtheria antitoxin, a hyperimmune antiserum produced in horses, protects against neurotoxicity when given within the first or second day of the illness. Prevention is accomplished by immunization with formalin-inactivated toxin, usually given within the first year of life.

Additional treatment of primary ocular infection includes topical erythromycin ointment, frequent manual removal of infected membranes, and ocular lubrication. Topical steroids may be used to reduce inflammation if no corneal ulceration is present.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Treatment includes supportive care and isolation, as well as penicillin or erythromycin, which are extremely effective against C diphtheriae.

Diphtheria antitoxin, a hyperimmune antiserum produced in horses, protects against neurotoxicity when given within the first or second day of illness. Prevention is accomplished by immunization with formalin-inactivated toxin, usually given within first year of life.

Additional treatment of primary ocular infection includes topical erythromycin ointment, frequent manual removal of infected membranes, and ocular lubrication. Topical steroids may be used to reduce inflammation if no corneal ulceration is present.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Drug Category: Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Patients should receive follow-up care until the conjunctivitis is resolved.

Deterrence/Prevention

• From 1991 through 1998, there was a massive epidemic of diphtheria in the Independent States of the Former Soviet Union, representing the first large-scale diphtheria outbreak in developed countries in more than 30 years. This occurred because of vaccine shortages and laxity in diphtheria immunization programs. Beginning in 1995, aggressive control strategies were implemented through mass vaccination with diphtheria toxoid, resulting in a major decrease in new cases of diphtheria by 2000.
• See related CME at Guidelines Issued on Pertussis, Tetanus, Diphtheria Prevention in Pregnant Women and Newborns.

Complications

• With severe respiratory involvement, death can occur.
• Optic neuritis has been reported as a possible rare complication of diphtheria immunization.

Prognosis

• The prognosis is favorable if detected early in the disease.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Although diphtheria is not endemic in the United States, do not fail to think of it when seeing patients outside the country or when examining patients who have recently arrived from nations in the third world.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Burkhard C, Choi M, Wilhelm H. [Optic neuritis as a complication in preventive tetanus-diphtheria-poliomyelitis vaccination: a case report]. Klin Monatsbl Augenheilkd. Jan 2001;218(1):51-4. [Medline].
• Chandler JW, Milam DF. Diphtheria corneal ulcers. Arch Ophthalmol. Jan 1978;96(1):53-6. [Medline].
• Coachman J. Diphtheric conjunctivitis. Mer J Ophth. 1951;34:1176.
• Dittmann S, Wharton M, Vitek C, et al. Successful control of epidemic diphtheria in the states of the Former Union of Soviet Socialist Republics: lessons learned. J Infect Dis. Feb 2000;181 Suppl 1:S10-22. [Medline].
• Fuchs E. Textbook of Ophthalmology. 1889.
• Hardy IR, Dittmann S, Sutter R. Current situation and control strategies for resurgence of diphtheria in Newly Independent States of the former Soviet Union. Lancet. 10/1996;347:1739-1744.
• Pichichero ME, Rennels MB, Edwards KM, et al. Combined tetanus, diphtheria, and 5-component pertussis vaccine for use in adolescents and adults. JAMA. Jun 22 2005;293(24):3003-11. [Medline].
• Rolleston JD. Diphtheric paralysis. Arch Pediatr. 1913;30:335-45.
• Rolleston JD, Ronaldson GW. Acute Infectious Diseases. 1940.
• Tharmaphornpilas P, Yoocharoan P, Prempree P, et al. Diphtheria in Thailand in the 1990s. J Infect Dis. Oct 15 2001;184(8):1035-40. [Medline].
• Walshe FMR. On the pathogenesis of diphtheric paralysis. Q J Med. 1918-19;12:14-37.

Article Last Updated: Nov 17, 2008