eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Diphtheria

Author: Cem S Demirci, MD, Fellow in Endocrinology, Children's Hospital of Pittsburgh
Coauthor(s): Walid Abuhammour, MD, FAAP, Associate Professor of Pediatrics, Michigan State University; Director of Pediatric Infectious Disease, Department of Pediatrics, Hurley Medical Center
Contributor Information and Disclosures

Updated: Jul 29, 2008

Introduction

Background

Diphtheria is an acute toxin-mediated disease caused by Corynebacterium diphtheriae. Nontoxigenic strains also cause disease, which is mostly cutaneous and usually mild. Three biotypes (ie, mitis, gravis, intermedius), each capable of causing diphtheria, are differentiated by colonial morphology, hemolysis, and fermentation reactions.

The "strangling angel of children," as diphtheria was once called, can be traced to the fourth-to-fifth century BC and was one of the most common causes of death among children in the prevaccine era. Klebs was the first to identify the organism in 1884, and Loeffler was first to cultivate the bacterium a year later. Roux and Yersin purified the toxin in 1889, and the antitoxin was invented shortly afterwards. In the 1920s, the toxoid was developed.

Unlike other diphtheroids (eg, coryneform bacteria), which are ubiquitous in nature, C diphtheriae is an exclusive inhabitant of human mucous membranes and skin. Spread primarily occurs via contact with airborne respiratory droplets, direct contact with respiratory secretions of symptomatic individuals, or contact with exudate from infected skin lesions. Asymptomatic respiratory carriers are important in transmission.

In the prevaccine era, diphtheria was a dreaded highly endemic childhood disease found in temperate climates. Despite a gradual decline in deaths in most industrialized countries in the early 20th century (associated with improving living standards), diphtheria remained one of the leading causes of death in children until widespread vaccination was implemented. In England and Wales, as recently as 1937-1938, diphtheria was second only to pneumonia among all causes of death in children, with an annual death rate of 32 per 100,000 in children younger than 15 years.

Superimposed on the high rates of endemic disease was a rough incidence periodicity that demonstrated peaks every several years. Epidemic waves were characterized by extremely high incidence in Spain in the early 1600s, New England in the 1730s, and Western Europe from 1850-1890. Deaths were sporadic.

The factors governing the periodicity of diphtheria outbreaks are not understood. In the United States, Canada, and many countries in Western Europe, the widespread use of diphtheria toxoid for childhood vaccination, beginning in the 1930s and 1940s, led to a rapid reduction in diphtheria incidence. However, in the 1930s, a gradual rise in diphtheria incidence to 200 cases per 100,000 in the prewar period occurred in Germany and several other central European countries with partially implemented vaccination programs. The onset of World War II in 1939 and the occupation by German troops of many Western European countries led to the last diphtheria pandemic in western industrialized countries.

Pathophysiology

Diphtheria organisms usually remain in the superficial layers of skin lesions or respiratory mucosa, inducing local inflammatory reaction. The organism's major virulence lies in its ability to produce the potent 62-kd polypeptide exotoxin, which inhibits protein synthesis and causes local tissue necrosis.

Diphtheriae toxin, which is secreted by toxigenic strains of C diphtheriae, is a single polypeptide of Mr 58,342. Toxigenic strains of C diphtheriae carry the tox structural gene found in lysogenic corynebacteriophages beta-tox +, gamma-tox +, and omega-tox +.

Highly toxic strains have 2 or 3 tox + genes inserted into the genome. Expression of the gene is regulated by the bacterial host and is iron dependent. In the presence of low concentrations of iron, the gene regulator is inhibited, resulting in increased toxin production. Toxin is excreted from the bacterial cell and undergoes cleavage to form 2 chains, A and B, which are held together by an interchain disulfide bond between cysteine residues at positions 186 and 201. As toxin concentrations increase, the toxic effects extend beyond the local area because of distribution of the toxin by the circulation. Diphtheriae toxin does not have a specific target organ, but myocardium and peripheral nerves are most affected.

Within the first few days of respiratory tract infection, a dense necrotic coagulum of organisms, epithelial cells, fibrin, leukocytes, and erythrocytes forms, advances, and becomes a gray-brown adherent pseudomembrane. Removal is difficult and reveals a bleeding edematous submucosa. Paralysis of the palate and hypopharynx is an early local effect of the toxin. Toxin absorption can lead to necrosis of kidney tubules, thrombocytopenia, cardiomyopathy, and demyelination of nerves. Because cardiomyopathy and demyelination of nerves can occur 2-10 weeks after mucocutaneous infection, the pathophysiologic mechanism may be immunologically mediated in some patients.

In the classic description of diphtheria, the primary focus of infection is the tonsils or pharynx in more then 90% of patients; the nose and larynx are the next most common sites. After an average incubation period of 2-4 days, local signs and symptoms of inflammation develop. Fever is rarely higher than 39°C.

Frequency

United States

Diphtheria cases remain isolated, with the last outbreaks reported between 1972-1982. Diphtheria incidence continued to decline steadily throughout the vaccine era in the United States and Western Europe (after the immediate postwar period). Cases of clinical diphtheria became extremely uncommon after the 1970s. Residual indigenous cases have been concentrated among incompletely vaccinated or unvaccinated persons of low socioeconomic status.

International

Diphtheria is endemic in many parts of the world, including countries of the Caribbean and Latin America. During the last 10 years, large epidemics of diphtheria have occurred in the former Soviet Union, where diphtheria had been well controlled. The largest outbreak of diphtheria in the developed world occurred from 1990-1995 throughout the states of the former Soviet Union.^1,2 Since 1994, with the initiation of aggressive immunization efforts, the number of reported cases has decreased. Outbreaks also have been reported in Central Asia, Algeria, and Ecuador.

A feature of these epidemics concerns the age group; most cases have occurred in adolescents and adults, rather than in children. Protocols in all countries of the European Union call for at least 3 doses of diphtheria vaccine during the first 2 years of life. Vaccination in France, Greece, Ireland, Luxembourg, Portugal, and the United Kingdom begins at age 2 months; in Austria, Belgium, Finland, Germany, Italy, the Netherlands, Spain, and Sweden vaccination begins at age 3 months; and in Denmark, it begins at age 5 months. Consecutive injections are usually separated by 1-2 months, but 9 months elapse between the second and third doses in Denmark.

Booster doses are administered in most countries 1 year after the third injection, then approximately every 5 years. Childhood immunization stops at age 6 years in Belgium, Ireland, Italy, and Portugal; at age 10 years in the Netherlands and Sweden; at age 15 years in Greece and Luxembourg; at age 15-19 years in the United Kingdom; and at age 18-20 years in France. Adult immunity, with tetanus toxoid and a low dose of diphtheria vaccine (Td) every 10 years, is maintained systematically only in Austria, Finland, and Germany. The epidemic of diphtheria in the former Soviet Union led the World Health Organization (WHO) to recommend systematic immunization of travelers to these countries.

Mortality/Morbidity

Death due to mechanical airway obstruction or cardiac involvement with circulatory collapse occurs in at least 10% of patients with respiratory tract diphtheria. The mortality rate has not improved and was approximately 20% in the outbreak that occurred in the newly independent states of the Soviet Union during the early 1990s.

Prognosis depends on the virulence of the organism (with the gravis strain usually accounting for the most severe disease), the age and immunization status of the patient, the site of involvement, and the speed with which antitoxin is administered. For patients in whom disease is recognized on day 1 and therapy is promptly initiated, the mortality rate is approximately 1%. If appropriate treatment is withheld until day 4, the mortality rate rises to 20%.

Diphtheria was no longer considered to be a child killer until large epidemics in several Eastern European countries drew attention to this forgotten disease in the 1990s. Reports from developing countries suggest that different epidemiologic patterns of the disease occur in populations with different immunization histories. The outbreaks had high case fatality rates and a large proportion of patients with complications.

Race

No racial predilection is observed.

Sex

No difference has been described for acute infection; however, in surveys from around the world, lack of immunity was more pronounced in elderly women than in men.

Age

When diphtheria was endemic, it primarily affected children younger than 15 years; recently, the epidemiology has shifted to adults who lack natural exposure to toxigenic C diphtheriae in the vaccine era and those who have low rates of receiving booster injections. In the 27 sporadic cases of respiratory tract diphtheria reported in the United States in the 1980s, 70% occurred in persons older than 25 years.

Data from Europe are particularly noteworthy because the childhood immunization rate exceeds 95% in some countries (eg, Sweden), but approximately 20% of persons younger than 20 years and as many as 75% of persons older than 60 years lack the protective antibody. Other broad serosurveys have identified large subgroups of underimmunized individuals in the United States and other countries in which immunization is believed to be universal; these individuals would be at risk if the organism were introduced. In serosurveys in the United States and other developed countries with almost universal immunization during childhood, such as Sweden, Italy, and Denmark, 25% to more than 60% of adults lacked protective antitoxin levels, with particularly low levels found in elderly persons.

Clinical

History

Severity of disease due to C diphtheriae depends on the site of infection, the immunization status of the patient, and the dissemination of toxin (which is influenced by administration of antitoxin). Initial infection usually is localized and is categorized by the site of involvement.

• Tonsils and pharynx: Tonsillar and pharyngeal diphtheria are most common; symptoms begin with a sore throat, usually in the absence of systemic complaints. Fever, if it occurs, is usually lower than 102°F, and malaise, dysphagia, and headache are not prominent features.
  • In individuals with diphtheria infection who are not immune, membrane formation begins after the 2-day to 5-day incubation period and grows to involve the pharyngeal walls, tonsils, uvula, and soft palate. The membrane may extend to the larynx and trachea, causing airway obstruction and eventual suffocation.
  • Underlying tissue of the throat and neck becomes edematous, and lymphadenopathy develops. Marked edema of the neck may lead to a bull-neck appearance with a distinct collar of swelling; the patient throws the head back to relieve pressure on the throat and larynx. Erasure edema associated with pharyngeal diphtheria obliterates the angle of the jaw, the borders of the sternocleidomastoid muscle, and the medial border of the clavicles. Swallowing may be made difficult by unilateral or bilateral paralysis of the muscles of the palate.
  • If toxin production is unopposed by antitoxin and severe disease occurs, early localized signs and symptoms give way to circulatory collapse, respiratory failure, stupor, coma, and death.
• Larynx: In a minority of patients, the larynx is the initial site of infection, with initial presenting symptoms similar to laryngotracheobronchitis from other causes. Initial hoarseness may progress to loss of voice and severe respiratory tract obstruction. Initially, nasal diphtheria may present as a common viral upper respiratory tract infection. A foul odor may develop. This form of diphtheria is most common in infants.
• Skin: Cutaneous diphtheria may occur at one or more sites, usually localized to areas of previous mild trauma or bruising. It is more common in tropical climates, but outbreaks have occurred in the United States. Pain, tenderness, and erythema at the site of infection progress to ulceration with sharply defined borders and formation of a brownish gray membrane. Local disease may persist for weeks to months.
• Other sites: Additional sites of infection have included the external ear, the eye (usually the palpebral conjunctivae), and the genital mucosa. Rare sporadic cases of endocarditis have been reported, usually due to nontoxigenic strains. Septicemia caused by C diphtheriae is rare but universally fatal.

Physical

Infection of the anterior nares (more common in infants) causes serosanguineous, purulent, erosive rhinitis with membrane formation. Shallow ulceration of the external nares and upper lip is characteristic. Mild pharyngeal infection is followed by unilateral or bilateral tonsillar membrane formation, which extends variably to affect the uvula, soft palate, posterior oropharynx, hypopharynx, and glottic areas. Underlying soft tissue edema and enlarged lymph nodes can cause a bull-neck appearance. The degree of local extension directly correlates with profound prostration, bull-neck appearance, and fatality from airway compromise or toxin-mediated complications. The leatherlike adherent membrane, extension beyond the faucial area, relative lack of fever, and dysphagia help differentiate diphtheria from exudative pharyngitis due to Streptococcus pyogenes and Epstein-Barr virus.

• Classic cutaneous diphtheria is an indolent nonprogressive infection characterized by a superficial, ecphymic, nonhealing ulcer with a gray-brown membrane. Diphtheritic skin infections cannot always be differentiated from streptococcal or staphylococcal impetigo, and they frequently occur together. In most patients, underlying dermatoses, lacerations, burns, bites, or impetigo have become contaminated secondarily. Extremities are affected more often than the trunk or head. Pain, tenderness, erythema, and exudate are typical. Local hyperesthesia or hypesthesia is unusual. Respiratory tract colonization or symptomatic infection and toxic complications occur in a minority of patients with cutaneous diphtheria.
• C diphtheriae occasionally causes mucocutaneous infections at other sites, such as the ear (otitis externa), eye (purulent and ulcerative conjunctivitis), and genital tract (purulent and ulcerative vulvovaginitis). Skin is the probable portal of entry, and almost all strains are nontoxigenic. Sporadic cases of pyogenic arthritis, mainly due to nontoxigenic strains, are reported in adults and children. Do not dismiss diphtheroids isolated from sterile body sites as contaminants without careful consideration of the clinical setting.
• Toxic cardiopathy occurs in approximately 10-25% of patients with diphtheria and is responsible for 50-60% of deaths.
• Neurologic complications parallel the extent of primary infection and are multiphasic in onset.

Causes

Among nonimmunized populations, diphtheria most often occurs during fall and winter, although summer outbreaks have occurred. Disease spreads more quickly and is more prevalent in poor socioeconomic conditions, where crowding occurs and immunization rates are low.

International travel could pose a risk to persons who are unvaccinated or inadequately vaccinated. The last case of fatal respiratory diphtheria in United States was reported in an unvaccinated Pennsylvania resident who had visited Haiti in October 2003.³

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