Introduction
Background
Diphtheria is caused by an aerobic, nonencapsulated, nonmotile, gram-positive bacillus Corynebacterium diphtheriae. The disease has been described in ancient records by Hippocrates as far back as the 5th century BC. Numerous epidemics swept through Europe over the ages. In the 18th century, diphtheria plagued the American colonies claiming a large number of victims. The number of deaths due to C diphtheriae did not fall dramatically until the 1940s with the introduction of diphtheria vaccine.
The bacterium exists as an exotoxin producing strain (tox+) and a nontoxigenic form (tox-). Three strains of C diphtheriae exist: gravis, intermedius, and mitis; each differs in the severity of disease they produce in humans. C diphtheriae typically provokes a localized mucosal infection of the upper respiratory tract; however, occasionally, it is responsible for a severe systemic disease mediated by the production of an exotoxin. Infection with the diphtheria bacillus may result in an active infection or a carrier state. Asymptomatic carriers may be reservoirs for active infections.
Corynebacterium ulcerans causes cutaneous diphtheria, a mild disease localized to the skin. This article discusses primarily the effects of diphtheria on the upper respiratory tract.
Pathophysiology
Humans comprise the only reservoir of infection. Carriers are usually asymptomatic. C diphtheriae spreads via respiratory droplets, contact with nasopharyngeal secretions, or wound exudates in cases of cutaneous disease. Rarely one may contract diphtheria via fomites. Overcrowding, poor health, and substandard living conditions facilitate the spread of the disease.
C diphtheriae is not a particularly invasive organism. It occupies the superficial layers of the respiratory tract and the skin causing local tissue inflammatory reaction followed by tissue necrosis. The occurrence of systemic disease depends on the elaboration of a potent exotoxin by tox+ strains. The diphtheria toxin is a 62,000-dalton polypeptide composed of 2 joined segments (A and B). The B fragment binds to a receptor on a susceptible cell and undergoes proteolytic cleavage, thus facilitating the entry of segment A, which inactivates RNA translocase. The process ultimately functions to inhibit protein synthesis in mammalian cells. The locally produced toxin is then carried via lymphatics and blood vessels to susceptible tissues. It exhibits a predilection for the myocardium and the cells of the nervous system.
Production of toxin by C diphtheriae is dependent on the presence of tox+ gene carried by a lysogenic beta-phage. Tox- strains can acquire toxigenicity following an infection with a lysogenic beta-phage. The transformation has been observed in vitro and in vivo.
Cases of a nontoxigenic strain of C diphtheriae causing invasive disease have been documented. In 2004, an otherwise healthy 38-year-old man in Poland developed septicemia and endocarditis following an infection with such a strain. The mechanism for the infection has not been elucidated as of yet.
Classically, diphtheria presents as a respiratory tract infection within the first few days of the onset of illness. It is characterized by the formation of a dense, gray pseudomembrane composed of a mixture of dead cells, fibrin, RBCs, WBCs, and organisms. Removal of the membrane reveals a bleeding, edematous mucosa. The distribution of the membrane varies from local (eg, tonsillar, pharyngeal) to widely covering the entire tracheobronchial tree. A combination of cervical adenopathy and swollen mucosa imparts a "bull's neck" appearance to the victims. The most frequent cause of death is suffocation following aspiration of the pseudomembrane.
Cutaneous diphtheria is a disease seen mostly, but not exclusively, in tropical regions. It is 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. Bacteria from cutaneous lesions have been found to cause pharyngeal infections and thus serve as a reservoir for infection.
Frequency
United States
In the prevaccine era, multiple cases affecting primarily children were seen in the winter months. The introduction of diphtheria toxoid in the 1940s dramatically reduced the incidence of this disease. Currently, only sporadic cases occur mainly if the Native American population.
The 1920s saw 140-150 cases per 100,000 population, with 206,000 cases reported in 1921 alone.
In 1945, 19,000 cases were reported.
From 1970-1979, 196 cases were reported annually, and starting in 1980, cutaneous cases due to nontoxigenic strains were no longer included in the reporting.
From 1980-2004, 57 cases of diphtheria were reported, but only 5 since 2000. The vast majority of these cases occurred in individuals lacking immunizations entirely or in those who were incompletely immunized.
In 2001, 2 probable cases of diphtheria (pharyngeal) were reported in Michigan and Montana. None of them were travel related.
In October 2003, a case of respiratory diphtheria was reported in Pennsylvania in a male traveling to Haiti. The patient was unvaccinated and did not recover from the disease.
Currently, diphtheria occurs sporadically mostly among the Native American population, homeless people, and alcoholics.
International
Diphtheria continues to occur in other parts of the world.
From 1990-1995, a diphtheria epidemic emerged in the Russian Federation rapidly spreading to involve all Newly Independent States (NIS) and Baltic States. This was the largest epidemic recorded since wide implementation of the vaccine program. Between 1990 and 1998 an excess of 157,000 cases were reported in those countries, accounting for more than 80% of cases reported worldwide. The vast majority of cases occurred among the adult population.
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.
In 2004, there was a case report in Poland of diphtheria with systemic involvement due to nontoxigenic strain of C diphtheriae.
In the 1980s and 1990s, outbreaks were reported in both industrialized (Germany, Sweden) and developing countries (China, Ecuador, Sudan, Thailand, Nepal).
Mortality/Morbidity
The most widely quoted diphtheria mortality rate is 5-10%. It may reach higher than 20% in children younger than 5 years. Disproportionately high rates of death were observed in individuals older than 40 years during an epidemic in the States of the former Soviet Union. Infection with the gravis strain is associated with higher mortality rates.
In the 1920s in the United States, 15,000 deaths were reported annually.
In the 1990-1998 NIS epidemic, 5,000 deaths were reported.
Mortality rates have not changed over the past few decades; most deaths occur on days 3-4 secondary to asphyxia with the membrane or myocarditis.
Mortality rates of 30-40% have been reported for bacteremic disease.
Race
No racial predilection for the disease is apparent.
Sex
No significant differences exist between the incidence of disease in males and females. In certain regions of the world, however, women may have lower immunization rates than males. Interestingly, women accounted for the majority of deaths in the epidemic in the Newly Independent States.
Age
Historically, diphtheria was primarily a disease of childhood affecting populations younger than 12 years. Infants became susceptible to the disease at age 6-12 months after their transplacentally derived immunity waned. Since the advent of diphtheria toxoid, cases of pediatric disease have declined dramatically. Recently, however, diphtheria has shifted into the adult population. This trend is largely due to incomplete immunization status or a total lack of it.
Clinical
History
- Onset of symptoms of respiratory diphtheria typically follows an incubation period of 2-5 days (range, 1-10 d). Symptoms are frequently general and nonspecific, often resembling viral upper respiratory infection (URI). Patients may present with the following:
- Low-grade fever (rarely >103°F) (50-85%) and chills
- Malaise, weakness, prostration
- Sore throat (85-90%)
- Headache
- Cervical lymphadenopathy and membrane 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 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.
Physical
- Cutaneous diphtheria begins as a painful lesion resembling an erythematous pustule, which breaks down to form an ulcer covered with a gray membrane.
- 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 be associated with dysphonia.
- Respiratory embarrassment may manifest itself 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 - Seen in as many as 60% of patients (especially if previously unimmunized); can present acutely with CHF, circulatory collapse, or in a more subtle way with progressive dyspnea, diminished heart sounds, cardiac dilatation, and weakness
- Atrioventricular blocks, ST-T wave changes, and various dysrhythmias
- Endocarditis
- Neurologic toxicity is proportional to the severity of the pharyngeal infection. Most patients with severe disease develop neuropathy. Deficits include the following:
- Regurgitation of swallowed fluids due to paralysis of the soft palate and posterior pharyngeal wall
- Oculomotor and ciliary paralysis accounting for cranial neuropathies
- Dysfunction of facial, pharyngeal, or laryngeal nerves
- Peripheral neuritis develops anywhere from 10 days to 3 months after the onset of pharyngeal disease. It manifests itself 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.
- Occasionally, a glove-and-stocking neuropathy pattern can be observed.
- All nerve damage due to diphtheria eventually resolves.
- Other systems involvement: Diphtheria is occasionally seen in the female genital tract, conjunctivae, or ear.
- Invasive disease may manifest as endocarditis, mycotic aneurysm, septic arthritis, or osteomyelitis. Nontoxigenic C diphtheriae has been implicated in all of the cases.
Causes
Increased risk for diphtheria infection includes the following factors:
- Incomplete or absent immunization, especially true for the adult population, but also for the pediatric population in underdeveloped countries. In some cases, immunity does not prevent infection but lessens the severity of the disease.
- Low herd immunity
- Travel to endemic areas or regions with current epidemics
- Immunocompromised state - Due to pharmacologic immune suppression, disease states including HIV, or relative compromise such as from diabetes or alcoholism
- Low socioeconomic status - Native American population is at an increased risk.
- Large-scale population movements - Implicated in the spread of the epidemic in the Newly Independent States of the former Soviet Union
- Poor healthcare care system infrastructure
- Overcrowding - Homeless shelters, jails
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Further Reading
Keywords
diphtheria, Corynebacterium diphtheriae, C diphtheriae, Corynebacterium ulcerans, mitis, intermedius, gravis, diphtheria vaccine, diphtheria toxoid
