eMedicine Specialties > Emergency Medicine > Infectious Diseases

Diphtheria

Author: Allysia M Guy, MD, Staff Physician, Department of Emergency Medicine, State University of New York Downstate Medical Center, Brooklyn, New York
Coauthor(s): Mark A Silverberg, MD, FACEP, MMB, Assistant Professor, Assistant Residency Director, Department of Emergency Medicine, State University of New York Downstate College of Medicine; Consulting Staff, Department of Emergency Medicine, Staten Island University Hospital, Kings County Hospital, University Hospital, State University of New York Downstate at Brooklyn
Contributor Information and Disclosures

Updated: Oct 5, 2009

Introduction

Background

C diphtheria is responsible for both endemic and epidemic diseases, and it was first described in the 5th century BC by Hippocrates. Diphtheria manifests as either an upper respiratory tract or cutaneous infection and is caused by the aerobic gram-positive bacteria, Corynebacterium diphtheria. The infection usually occurs in the spring or winter months. It is communicable for 2-6 weeks without antibiotic treatment.^1,2 People who are most susceptible to infection are those who are not completely immunized or have low antitoxin antibody levels and have been exposed to a carrier or diseased individual. A carrier is someone whose cultures are positive for the diphtheria species but does not exhibit signs and symptoms. Studies show that as the number of asymptomatic carriers decrease, the number of diphtheria cases consequently decline.^1,3

C diphtheria is a nonencapsulated, nonmotile, gram-positive bacillus; this is shown in the image below. Pathogenic strains can result in severe localized upper respiratory infection, localized cutaneous infections, and rarely systemic infection.

Pathophysiology

Overcrowding, poor health, substandard living conditions, incomplete immunization, and immunocompromised states facilitate susceptibility to diphtheria and are risk factors associated with transmission of this disease.⁶ Human carriers are the main reservoir of infection; however, case reports have linked the disease to livestock.^5,4 Infected patients and asymptomatic carriers can transmit C diphtheria via respiratory droplets, nasopharyngeal secretions, and rarely fomites.^1,2 In the case of cutaneous disease, contact with wound exudates may result in the transmission of the disease to the skin as well the respiratory tract.⁴

Immunity from exposure or vaccination wanes over time. Inadequate boosting of previously vaccinated individuals may result in increased risk of acquiring the disease from a carrier, even if adequately immunized previously. Additionally, since the advent of widespread vaccination, cases of nontoxigenic strains causing invasive disease have increased.⁷

C diphtheria adheres to mucosal epithelial cells where the exotoxin, released by endosomes, causes a localized inflammatory reaction followed by tissue destruction and necrosis. The toxin is made of two joined proteins.² The B fragment binds to a receptor on the surface of the susceptible host cell, which proteolytically cleaves the membrane lipid layer enabling segment A to enter.¹ Molecularly, it is suggested that the cellular susceptibility is also due to diphthamide modification, dependent on human leukocyte antigen (HLA) types predisposing to more severe infection. The diphthamide molecule is present in all eukaryotic organisms and is located on a histidine residue of the translation elongation factor 2 (eEF2). eEF2 is responsible for the modification of this histidine residue and is the target for the diphtheria toxin (DT).

Fragment A inhibits an amino acid transfer from RNA translocase to the ribosomal amino acid chain, thus inhibiting protein synthesis is required for normal host cell functioning.¹ DT causes a catalytic transfer of NAD to diphthamide, which inactivates the elongation factor, resulting in the inactivation eEF2, which results in protein synthesis blockage and subsequent cell death.^8,2

Local tissue destruction enables the toxin to be carried lymphatically and hematologically to other parts of the body. Elaboration of the diphtheria toxin may affect distant organs such as the myocardium, kidneys, and nervous system. Nontoxigenic strains tend to produce less severe infections; however, since widespread vaccination, case reports of nontoxigenic strains of C diphtheria causing invasive disease have been documented.¹

Frequency

United States

Since the introduction and widespread use of diphtheria toxoid in the 1920s, respiratory diphtheria has been well controlled, with an incidence of approximately 1000 cases reported annually. Before vaccination, at least 200,000 cases occurred annually in the United States.⁹

Diphtheria remained endemic in some states through the 1970s, with reported incidence rates of greater than 1.0 per million population in Alaska, Arizona, Montana, New Mexico, South Dakota, and Washington.¹ Most of these infections were attributed to incomplete vaccination.

In the United States, diphtheria currently occurs sporadically, mostly among the Native American population, homeless people, lower socioeconomic groups, and alcoholics.⁶ Immigrants and travelers from regions with ongoing epidemics are also at risk.⁶

International

According to the World Health Organization (WHO), diphtheria epidemics remain a health threat in developing nations.² The largest epidemic recorded since widespread implementation of vaccine programs was in 1990-1995, when a diphtheria epidemic emerged in the Russian Federation, rapidly spreading to involve all Newly Independent States (NIS) and Baltic States. This epidemic caused more than 157,000 cases and 5000 deaths according to WHO reports.^10,11 Disproportionately high rates of death were observed in individuals older than 40 years, and 5,000 deaths were reported. This epidemic accounted for 80% of cases reported worldwide during this time period.¹²

From 1993-2003, a decade long epidemic in Latvia resulted in 1359 reported cases of diphtheria with 101 deaths. The incidence fell from 3.9 cases per 100,000 cases in 2001 to 1.12 cases per 100,000 population in 2003. Most cases were registered in unvaccinated adults.

From 1995-2002, 17 cases of cutaneous diphtheria due to toxigenic strains were reported in the United Kingdom.¹²

Many case reports in the literature describe epidemics in sub-Saharan Africa, France, India, and the United States.^13,14

Mortality/Morbidity

Before the introduction of vaccine in the 1920s, the incidence of respiratory disease was 100-200 cases per 100,000 population in the United States and has decreased to approximately 0.001 cases per 100,000 population.^9,1

The most widely quoted diphtheria mortality rate is 5-10%. It may reach higher than 20% in children younger than 5 years and adults older than 40 years. Immunization patterns have the most influence on mortality patterns. Mortality rates have not changed significantly over the past few decades. Most deaths occur on days 3-4 secondary to asphyxia with a pharyngeal membrane or due to myocarditis. Mortality rates of 30-40% have been reported for bacteremic disease.⁹

Race

No racial predilection for diphtheria has been reported.

Sex

No significant differences exist between the incidence of diphtheria in males and females. In certain regions of the world, however, women may have lower immunization rates than males. Female infants and young children account for the majority of deaths in endemic regions.

Age

Historically, diphtheria has been primarily a disease of childhood, affecting populations younger than 12 years. Infants become susceptible to the disease at age 6-12 months after their transplacentally derived immunity wanes.¹⁵ Since the advent of diphtheria vaccination, cases of pediatric disease have declined dramatically. Recently, however, diphtheria has shifted into the adolescent and adult population, most notably in ages 40 and older accounting for most new cases.¹¹ This is primarily due to incomplete immunization status, including never being immunized, inefficient vaccine or response to vaccination, and not receiving a booster after previous vaccination. According to immunologic studies, one must have an antitoxin level of greater 0.1 IU/mL for adequate immunity.¹⁶ Additionally, adolescents and adults may exhibit an atypical presentation of the disease, thus potentially obscuring the diagnosis.⁷

Immunization schedules have recently changed requiring a toxoid booster at age 11-12 and every 10 years thereafter. The toxoid booster, without tetanus, is approved for pregnant women if their antitoxin titers are less than 0.1 IU/mL.^17,16

Clinical

History

Onset of symptoms of respiratory diphtheria typically follows an incubation period of 2-5 days (range, 1-10 d).^9,1 Symptoms initially are general and nonspecific, often resembling a typical viral upper respiratory infection (URI). Respiratory involvement typically begins with sore throat and mild pharyngeal inflammation. Development of a localized or coalescing pseudomembrane can occur in any portion of the respiratory tract. The pseudomembrane is characterized by the formation of a dense, gray debris layer composed of a mixture of dead cells, fibrin, RBCs, WBCs, and organisms; the pseudomembrane is shown in the image below.

Cutaneous diphtheria is a disease characterized by indolent, nonhealing ulcers covered with a gray membrane. The ulcers are often co-infected with Staphylococcus aureus and group A streptococci. This form of the disease is seen with increasing frequency in poor inner-city dwellers and alcoholics. The lesions of cutaneous diphtheria are infectious, and bacteria from cutaneous lesions have been found to cause pharyngeal infections and thus serve as a reservoir for infection.

• Patients with diphtheria may present with the following complaints
  • Low-grade fever (rarely >103°F) (50-85%) and chills
  • Malaise, weakness, prostration
  • Sore throat (85-90%)
  • Headache
  • Cervical lymphadenopathy and respiratory tract pseudomembrane formation (about 50%)
  • Serosanguineous or seropurulent nasal discharge, white nasal membrane
  • Hoarseness, dysphagia (26-40%)
  • Dyspnea, respiratory stridor, wheezing, cough
• Respiratory diphtheria may quickly progress to respiratory failure due to airway obstruction or aspiration of pseudomembrane into the tracheobronchial tree.
• Cutaneous diphtheria often develops at a site of previous trauma or a primary dermatologic disease. It follows an indolent course, typically lasting weeks to months. Occasionally, it may cause respiratory diphtheria.¹⁵

Physical

General: Patient has a low-grade fever but is toxic in appearance, and also may have a swollen neck.

Pharyngeal diphtheria:

• Patients may present with general symptoms of fever, halitosis, tachycardia, and anxiety.
• Tonsils and pharynx: Pharyngeal erythema and edema, thick, gray, leathery membrane variably covers the tonsils, soft palate, oropharynx, nasopharynx, and uvula. Attempts at scraping the pseudomembrane causes bleeding of the underlying mucosa.
• Neck: Extensive anterior and submandibular cervical lymphadenopathy imparts a bull's neck appearance. The patient may hold his or her head in extension. It can occasionally also be associated with dysphonia.
• Respiratory distress manifesting as stridor, wheezing, cyanosis, accessory muscle use, and retractions.

Cardiac toxicity typically occurs after 1-2 weeks of illness following improvement in the pharyngeal phase of the disease. It may manifest as follows:

• Myocarditis is seen in as many as 60% of patients (especially if previously unimmunized) and can present acutely with congestive heart failure (CHF), circulatory collapse, or more subtly with progressive dyspnea, diminished heart sounds, cardiac chamber dilatation, and weakness.¹⁸
• Atrioventricular blocks, ST-T wave changes, and various dysrhythmias may be evident.
• Endocarditis may be present.

Neurologic toxicity is proportional to the severity of the pharyngeal infection. Most patients with severe disease develop neuropathy. Deficits include the following:

• Cranial nerve deficits including oculomotor, ciliary paralysis, facial, and pharyngeal, or laryngeal nervous dysfunction.
• Occasionally, a stocking and glove peripheral sensory neuropathy pattern can be observed.
• Most C diphtheriae associated neurologic dysfunction eventually resolves.
• Peripheral neuritis develops anywhere from 10 days to 3 months after the onset of pharyngeal disease. It manifests initially as a motor defect of the proximal muscle groups in the extremities extending distally. Various degrees of dysfunction exist, ranging from diminished DTRs to paralysis.¹⁹
• Other systems involvement: Diphtheria is occasionally seen in the female genital tract, conjunctivae, or ear.
• Invasive disease may manifest in multiple organ system disease, though this is rare.^1,3
• Cutaneous diphtheria begins as a painful lesion resembling an erythematous pustule, which breaks down to form an ulcer covered with a gray membrane.^4,15

Causes

The following factors may predispose to diphtheria infection:

• Incomplete or absent immunization, which is especially important in the adult population, and as well the pediatric population in underdeveloped countries, may predispose to infection. In some cases, immunity does not prevent infection but lessens the severity of the disease.⁹
• Antitoxin titers decrease over time and immunity wanes, thus older people who have not received booster vaccination are more susceptible to contract the disease from carriers. Studies suggest if titer level is greater than 0.1 UI/mL, then an individual is characterized as immune from infection.
• Low herd immunity, possibly leading to increasing prevalence of diphtheria infections
• Travel to endemic areas or regions with current epidemics
• Immunocompromised states - Due to pharmacologic immune suppression, disease states including HIV, or relative compromise such as from diabetes or alcoholism
• Low socioeconomic status
• Large-scale population movements - Implicated in the spread of the epidemic in the Newly Independent States of the former Soviet Union²⁰
• Poor healthcare care system infrastructure
• Overcrowding - Homeless shelters, jails

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