by Rachel Osborne

Ø   Disease: Diphtheria, caused by a toxic strain of Corynebacterium diphtheria (1). Toxic strains of Corynebacterium ulcerans can also cause diphtheria-like symptoms (2).

Ø   Transmission: The disease if most often transmitted through contact with an infected human host (1, 2). Respiratory diphtheria is spread through airborne droplets or other close contact with respiratory membranes (2), and cutaneous diphtheria is spread through direct contact with skin lesions of an infected host (2). On rare occasions, diphtheria can be transmitted through indirect contact (fomites), and transmission can also occur through food vehicles such as milk or other dairy products (2, 3).


Ø   Reservoirs: The only confirmed reservoirs or diphtheria are humans (2, 4); thus, reproducing colonies of C. diphtheria have neither been found in animals nor non-living reservoirs such as soil, water, air, and food.


Ø   General Characteristics of MO: The C. diphtheria bacterium is a gram positive rod with a distinct club shape at one end of the rod (4, 5), and also has metachromatic granules (5,6). It is nonmotile, a facultative anaerobe (5) and is also catalase positive. The bacteria also ferment glucose and maltose, and one of the three strains, mitis, also ferments starch (6). Due to the fermentation of carbohydrates, these bacteria seem to be chemoheterotrophic.


Ø    Key tests for identification: The toxigenic strain of C. diphtheria is often detected by PCR amplification of a bacterial culture; the PCR detects the presence of the tox gene, a 248 bp band, which codes for the production of the toxin (4, 7). Enzyme immunoassays (e.g., ELISA) are also used to detect for the presence of the toxin (4, 7). In such tests, an equine polyclonal antitoxin may be used to bind to the toxin, which then binds to a monoclonal antitoxin that is linked to an enzyme such as alkaline phosphatase (7). If the enzyme shows activity when a substrate is added, it can be concluded that the toxin is present. Guinea pigs challenges are also used to identify toxigenic C. diphtheria, and involve the injection of a bacterial culture into guinea pigs and the observation of diphtheria-like symptoms in the guinea pigs (4,6).


Ø   Signs and symptoms of disease: The disease is usually manifested in two forms—either respiratory or cutaneous diphtheria (1, 8).


o        Respiratory diphtheria is caused by the infection of mucous membranes of the airways (2), and symptoms usually include a sore throat, mild fever, and hoarseness (2), as well as fatigue and a loss of appetite (8).  A gray membranous growth (i.e., pseudomembrane) consisting of toxin, dying tissue, fibrin, dead lymphocytes forms on the tonsils, pharynx, and/or inside the nose (1, 4). The membrane will bleed if attempts are made to remove it (4).  Signs and symptoms usually develop after an incubation period of 2-5 days (3). Substantial membranous growth can be problematic and potentially fatal if it obstructs the airways. In extreme cases, respiratory form is also characterized by a swollen neck, or “bull neck” (1, 2), which is due to cervical lymphadenopathy (2). Respiratory diphtheria can also result in a systemic infection, causing myocarditis-explain (2), and neuropathy-explain, (2). The neural complications generally involve destruction of motor neurons in the peripheral nervous system, which leads to a loss of motor control (5); meningitis and encephalitis (inflammation of brain tissue) can also occur in some cases (4).


o        Cutaneous diphtheria is less serious than the respiratory form (1), and its primary symptom is the formation of nonspecific lesions on the skin—often in pustular or vesicular form (4). The skin may also develop a bluish hue (3). The lesions are usually painful and will subside in approximately 14 days (5).


Death is generally caused by respiratory rather than cutaneous diphtheria, but is still rare, as only about 5-10% of cases are fatal (2). Most people die from obstruction of the air ways or cardiac and neural complications, and death occurs within one week of the onset of the symptoms (4).


Ø   Historical Information:  It is believed that the diphtheria was first described and reported by Hippocrates in 4 B.C. (9). Prior to the development of the vaccination, the diphtheria was a common cause of childhood mortality and a major concern to families (9). Due to the obstruction of the airways, the disease was often called the “Strangling Angel of Children” (4). A severe outbreak occurred in 1735 in New England, with many families losing all of their children to the disease (9). That year, approximately 5,000 people, or 2.5% of the population, died of diphtheria, and the mortality rate in children was nearly 80% (9). Another epidemic occurred in the late 1800s in New York with nearly 15,000 deaths in a period of 10 years (4). The etiologic agent was discovered in 1873 by Kleb (9), and in 1890, von Behring and Kitasato, discovered that horses produce antibodies when injected with sublethal doses of the toxin from infected horses (4,9); this discovery won von Behring the first Novel Prize in 1901 (9). In the early 1900s, scientists discovered that the toxin could be inactivated with heat and formalin, and that the inactivated form, or toxoid, caused the production of neutralizing antibodies in humans (4, 9). The toxoid vaccine was available in the US in 1920 and became available worldwide after WWII (4, 9).


Ø   Virulence Factors:  The primary virulence factor of C. diphtheria is an endotoxin that is released by the bacteria once inside the human host (1-5). The toxin is an AB toxin, with active and binding components, and is actually acquired via lysogenic conversion (4). That is, the tox gene, which codes for the toxin, is part of the corynebacteriophage genome and becomes integrated into the C. diphtheria chromosome when the phage undergoes lysogenic replication within the bacteria (4). The toxin’s pathogenic function is to inhibit protein synthesis within the cells of the human host, eventually leading to cell death (4). The tox gene is contained within a repressible operon and its transcription is turned off by high levels of iron (4). Iron binds to the repressor, which prevents transcription. There are also three strains of toxigenic C. diphtheria-gravis, intermedius, and mitis, with gravis being the most virulent; the gravis strain has a mechanism to deplete iron within the blood of the host, which enhances the expression of the tox gene (4).


Ø   Control/Treatment:  The primary treatment for diphtheria is a diphtheria antitoxin (DAT) that is derived from horses (4). DAT is more effective if administered immediately after the disease is detected, and is therefore given in larger doses and for a longer period of time when the disease has already manifested itself for a period of time (4). The next best treatment strategy is the use of antibiotics; penicillin and erythromycin are most effective and are administered for a period of about 14 days (4). In some cases, patients who are hospitalized may be intubated and receive oxygen and IV fluids (7).


Ø   Prevention/New Research: The standard prevention for diphtheria is vaccine, which first became available in the 1940s in the US and joined the series of standard childhood immunizations in the 1980s (1,4). The vaccine for diphtheria (DPT) is actually a combination of vaccines for diphtheria, tetanus, and pertussis. The vaccine is a toxoid (4), or a small dose of a deactivated, nonpathogenic form of the toxin that is still recognized as an antigen by the body’s immune system.  The vaccine must be administered multiple times throughout childhood: ages 2, 4, and 6 months, between 15-18 months, and at 4-6 years (4). It is also recommended that people receive a booster vaccine every ten years to maintain an effective defense against the infection (4). The vaccine does not confer absolute immunity, as people who receive the vaccine often are carriers of the disease but do not display symptoms (4). People who travel to countries where immunization rates are low and where diphtheria is endemic should ensure that they are vaccinated and/or are taking regular booster vaccines (4).


Ø   Current Local Outbreaks: In the US, after the introduction of the vaccine in 1980, there has been an average of 0.001 new cases per 100,000 people each year, or 1 case per 100 million people! (1). Before the vaccine, there were between 100-200 new cases/100,000 people each year (1). As a result of the prevention efforts, there has not been a new case of diphtheria in the US since 2003 (i.e., no one in the US currently has diphtheria) (2,10). In fact, this man was not vaccinated and had recently returned from a country in which diphtheria was endemic (2, 10), and therefore it is likely that he contracted the infection outside of the US.


Ø   Current Global Outbreaks:  Diphtheria is more prevalent in less developed countries where citizens are either unvaccinated or partially vaccinated. Such is the case in Russia and countries of the former Soviet Union (1). Several outbreaks have occurred there since the 1990s, with 150,000 reported cases between 1990 and 1995.The disease has now reached endemic status (1), and the current incidence rate in Russia is about 0.5 cases per 100,000 people (11). The worldwide prevalence in 2006 was approximately 17,000 cases (12).




1. Coordinating Center for Infectious Diseases: Division of Bacterial and Mycotic Diseases. “Diphtheria”. 10/5/05. URL: http://www.cdc.gov/ncidod/dbmd/diseaseinfo/diphtheria_t.htm accessed on 4/22/08.


2.  Center for Disease Control. “Traveler’s Health: Yellow Book Chapter 4: Prevention of Specific Infectious Disease”. 4/17/08. URL: http://www.cdc.gov/travel/yellowBookCh4-Diphtheria.aspx accessed on 4/23/08.


3. American Accreditation Healthcare Commission. “Diphtheria”. 9/25/06. URL:  http://www.hlm.hih.gov/medlineplus/ency/article/001608.htm accessed on 4/14/08.


4. Frassetto, L. A. “Corynebacterium infections”. 4/24/06. URL: www.emedicine.com/med/TOPIC459.HTM. accessed on 4/30/08.


5.  Public Health Agency of Canada. “Infectious Diseases”. 1/31/01. URL: http://www.phac-aspc.gc.ca/msds-ftss/msds42e.html accessed on 5/3/08. 


6. Murphy, J. R. “Corynebacterium diphtheria”. URL: http://gsbs.utmb.edu/microbook/ch032.htm accessed on 5/3/08.


7.  Angler, K. H., & Efstratiou, A. (2000). Rapid enzyme immunoassay for determination of toxigenicity among clinical isolates of corynebacteria. Journal of Clinical Microbiology, 38, 1385-1389.


8. National Foundation for Infectious Diseases. “Diphtheria Overview”. 2005. URL: www.nfid.org/powerof10/section3/overview-diphtheria.html accessed on 5/3/08.


9. English, P. (1985). Diphtheria and theories of infectious disease: Centennial appreciation of the critical role of diphtheria in the history of medicine. Pediatrics, 76, 1-9.


10. Center for Disease Control. “Fatal respiratory diphtheria in a U.S. traveler to Haiti: Pennsylvania, 2003.” 1/22/04. URL: http://www.medscape.com/viewarticle/467049 accessed on 4/30/08.


11.  Seward, J. “Epidemiology of Measles, Polio, and Diphtheria United States”. 4/24/07. URL: http://www.fda.gov/CBER/summaries/ig042507js.pdf accessed on 5/3/08.


12.  Todar, K. “Todar’s Online Textbook of Bacteriology: Diphtheria”. 2008. URL: http://www.textbookofbacteriology.net/diphtheria.html accessed on 5/3/08.