Diphtheria

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Diphtheria is a highly-contagious disease caused by Corynebacterium diphtheriae, an aerobic Gram-positive bacterium. It is generally an upper respiratory tract illness characterized by sore throat, low-grade fever, and an adherent membrane (a pseudomembrane) on the tonsil(s), pharynx, and/or nose. A milder form of diphtheria can be limited to the skin.

Diphtheria is spread by direct physical contact or breathing the secretions of those infected. Diphtheria was once quite common, but has largely been eradicated in developed nations. In the United States for instance, fewer than five cases a year have been reported since 1980 because the DPT vaccine (a mixture of three vaccines to immunize against diphtheria, pertussis, and tetanus) is given to all school children. Boosters of the vaccine are recommended for adults because the benefits of the vaccine decrease with age; public health officials recommend them in particular for people who travel to areas where the disease has not been eradicated yet.

As with polio, malaria, tuberculosis, and other diseases, the use of animals has proven instrumental in research and treatment related to diphtheria. This brings to the forefront the issue of the use of animals in medical research. In utilizing animals for research, testing, and vaccine production, when necessary for the greater good, humans have a responsibility to care for the welfare of the animals as best as possible given the circumstances, and to establish and follow regulations and guidelines to ensure compliance with ethical standards.

Contents

Name

Diphtheria takes its name from the Greek word for “leather,” διφθερα (dipthera), and was named in 1826 by French physician Pierre Bretonneau. The name alludes to the leathery, sheath-like membrane that grows on the tonsils, throat, and in the nose. Many writers today use the spelling diptheria, which fits the modern pronunciation, but cannot be found in dictionaries.

Signs and symptoms

The respiratory form has an incubation period (the time elapsed between exposure to the bacterium and when symptoms and signs first appear) of two to five days. The onset of disease is usually gradual. Symptoms include fatigue, fever, a mild sore throat, and problems swallowing. Children infected with the disease also experience nausea, vomiting, chills, and a high fever, although some do not show symptoms until the infection has progressed further. In ten percent of cases, patients experience neck swelling. These cases are associated with a higher risk of death.

In addition to symptoms at the site of infection, the throat, the patient may experience more generalized symptoms, such as listlessness, pallor, and fast heart rate. These symptoms are caused by the toxin released by the bacterium. Individuals with the disease may develop low blood pressure. Longer-term effects of the diphtheria toxin include cardiomyopathy (deterioration of the function of the heart muscle) and peripheral neuropathy (damage to nerves of the peripheral nervous system).

The cutaneous form of diphtheria affects the skin and is often a secondary infection of a preexisting skin disease. Signs of cutaneous diphtheria infection develop an average of seven days after the appearance of the primary skin disease.

Diagnosis

The current definition of diphtheria used by the U. S. Centers for Disease Control and Prevention (CDC) is based on both laboratory and clinical criteria.

The laboratory criteria for diagnosis are:

  • Isolation of Corynebacterium diphtheriae from a clinical specimen; or
  • Histopathologic diagnosis of diphtheria.

The clinical criteria for diagnosis are:

  • Upper respiratory tract illness with sore throat;
  • Low-grade fever; and
  • An adherent membrane of the tonsil(s), pharynx, and/or nose.

Cases may be classified as probable or confirmed:

  • Probable—a clinically compatible case that is not laboratory confirmed and is not epidemiologically linked to a laboratory-confirmed case;
  • Confirmed—a clinically compatible case that is either laboratory confirmed or epidemiologically linked to a laboratory-confirmed case.

Treatment is generally started in probable cases.

Treatment

The disease may remain manageable, but in more severe cases lymph nodes in the neck may swell, causing breathing and swallowing to become more difficult. People in this stage should seek immediate medical attention, as obstruction in the throat may require intubation (placing a tube in the trachea, commonly called the windpipe) or a tracheotomy (to open a direct airway through an incision in the trachea). In addition, an increase in heart rate may cause cardiac arrest.

Diphtheria can also cause paralysis in the eye, neck, throat, or respiratory muscles. Individuals with severe cases are put in a hospital intensive care unit (ICU) and given a diphtheria antitoxin. Since antitoxin does not neutralize toxin that is already bound to tissues, delaying its administration is associated with an increase in mortality risk. Therefore, the decision to administer diphtheria antitoxin is based on clinical diagnosis, and does not have to await laboratory confirmation.

Research has shown that antibiotics do not promote healing of local infection in diphtheria patients treated with antitoxin. Instead, antibiotics are given to individuals suffering from the disease, or carriers, to eradicate the bacterium C. diphtheriae and prevent its transmission to other people. The Centers for Disease Control (CDC) recommends either:

  • Erythromycin (orally or by injection) for 14 days (40 mg/kg per day with a maximum of 2 g/d), or
  • Procaine penicillin G given intramuscularly for 14 days (300,000 U/d for individuals weighing <10 kg (22 lb) and 600,000 U/d for those weighing >10 kg).

People who are allergic to penicillin G or erythromycin are given an alternative antibiotic, such as rifampin or clindamycin.

Epidemiology

Diphtheria remains a serious disease, with fatality rates between five and 10 percent in adults. In children under five years old and adults over 40 years old, the fatality rate may be as high as 20 percent. Outbreaks, though very rare, still occur worldwide, even in developed nations. After the breakup of the former Soviet Union in the late 1980s, vaccination rates in its constituent countries fell so low that there was an explosion of diphtheria cases. Between 1990 and 1998, the countries of the former Soviet Union reported more than 150,000 cases and 5,000 deaths, which represented more than 80 percent of diphtheria cases reported globally (Dittmann 2000). It was the largest diphtheria epidemic since the 1950s, when widespread diphtheria immunization began.

According to CDC guidelines, cases of cutaneous diphtheria should not be reported, while cases of the disease caused by nontoxigenic C. diphtheriae should be reported as diphtheria. The agency also recommends that all diphtheria isolates be sent to the CDC's diphtheria laboratory.

The Schick test can be used to test susceptibility (Venes 2005). The test was invented by Hungarian-born American pediatrician Béla Schick (1877-1967) in the early twentieth century to determine whether a person is susceptible to diphtheria. For the test, a small amount (0.1 ml) of diluted (1/50 MLD) diphtheria toxin is injected intradermally into the arm of an individual. If the skin around the injection becomes red and swollen (a positive result), it indicates that the person does not have enough antibodies to fight off the disease. The swelling disappears after a few days. Little or no swelling and redness occur in people who are immune, indicating a negative result.

History

Diphtheria was once one of the most dreaded diseases, with frequent large-scale outbreaks. A diphtheria epidemic in the New England colonies between 1735 and 1740 was said to have killed as many as 80 percent of the children under ten years of age in some towns. In the 1920s, there were an estimated 100,000 to 200,000 cases of diphtheria per year in the United States, with 13,000 to 15,000 deaths. Children represented the large majority of cases and fatalities.

A bottle of diphtheria antitoxin, produced by the United States Hygienic Laboratory and dated May 8, 1895

One of the first early effective treatments was discovered in the 1880s by U.S. physician Joseph O'Dwyer (1841-1898). O'Dwyer developed tubes that could be inserted into the throat to prevent victims from suffocating from the membrane sheath that grew and obstructed the airways.

In 1883, the bacterium that causes diphtheria, Corynebacterium diphtheriae, was first described, by Theodor Klebs. In 1884, Friedrich Loffler isolated C. diptheriae and injected it into various animals, proving that it was the agent that caused diphtheria. Subsequently, the fluid in which the bacteria grew was injected, after removal of the bacteria, into various animals (guinea pigs, rabbits, dogs, horses, and cats) and exhibited the effects of the toxin released by the bacteria (Roux and Yersin 1888).

In the 1890s, the German physician Emil von Behring developed an antitoxin that, although it did not kill the bacteria, neutralized the toxic poisons that the bacteria released into the body. For this discovery and his development of a serum therapy for diphtheria, he won the first Nobel Prize in Medicine. (Americans William H. Park and Anna Wessels Williams also developed a diphtheria antitoxin in the 1890s.) Horses were utilized to produce antitoxin on a large scale.

The first successful vaccine for diphtheria was developed in 1923. (Previously, von Behring has demonstrated long lasting immunity in various animals by using the antitoxin and toxin. But widespread immunization began after a formalin-inactivated toxin was developed.) Guinea pigs were used to standardize the vaccine. However, effective vaccines were not developed until the discovery and development of sulfa drugs (sulphur-containing drugs) following World War II.


Diphtheria was also prevalent in the British royal family during the late nineteenth century. Famous cases included a daughter and granddaughter of Britain's Queen Victoria. Princess Alice of Hesse (second daughter of Queen Victoria) died of diphtheria after she contracted it from her children in December of 1878 while nursing them. One of Princess Alice's daughters, Princess Marie, also died of diphtheria in November of 1878.

Sacagawea and Elisha Graves Otis also died from diphtheria.

References

  • Baron, S. 1996. Medical Microbiology, 4th ed. Galveston, TX: University of Texas Medical Branch.
  • Centers for Disease Control and Prevention (CDC). 1995. Diphtheria (Corynebacterium diphtheriae): 1995 Case Definition. http://www.cdc.gov/epo/dphsi/casedef/diphtheria_current.htm. Parts of this article originally were adapted from the CDC's case definition.
  • Dittmann, S., et al. 2000. "Successful Control of Epidemic Diphtheria in the States of the Former Union of Soviet Socialist Republics: Lessons Learned." The Journal of Infectious Diseases 181:S10-S22
  • Kasper, D. L., et al. 2005. Harrison's Principles of Internal Medicine, 16th ed. New York: McGraw-Hill Professional. ISBN 0071391401
  • Neuromuscular Disease Center at Washington University, St. Louis, M.O. Toxic Neuropathies: clinical and pathological features. [1] (accessed October 1, 2006)
  • RDS. [RDS http://www.rds-online.org.uk/pages/page.asp?i_ToolbarID=3&i_PageID=66 Diphtheria vaccine].
  • Roux, P., and A. Yersin. 1888. "Contribution al'etude de la diphtherie." Ann l Inst Pasteur 2: 629-661.
  • Soanes, C., and A. Stevenson. 2005. Oxford Dictionary of English. Oxford: Oxford University Press.
  • Venes, D. 2005. Taber's Cyclopedic Medical Dictionary, 20th ed. Philadelphia, PA: F. A. Davis Company. ISBN 0803612095


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