Diphtheria

by Sylvain Nawessi

Diphtheria; etiological agent - Corynebacterium diphtheriae  (2).

Transmission:

Through direct physical contact or breathing the aerosolized secretions of infected individuals (2).

Reservoir:

Infected adolescents and adults

General Characteristics:

In order to accurately identify C. diphtheriae, a Gram stain is performed to show gram-positive, highly pleomorphic organisms with no particular arrangement. Special stains like Alberts's stain and Ponder's stain are used to demonstrate the metachromatic granules formed in the polar regions. The granules are called as polar granules, Babes Ernst Granules, Volutin, etc. An enrichment medium, such as Löffler's medium, is used to preferentially grow C. diptheriae. After that, use a differential plate known as tellurite agar, which allows all Corynebacteria (including C. diphtheriae) to reduce tellurite to metallic tellurium. The tellurite reduction is colormetrically indicated by brown colonies for most Cornyebacteria species or by a black halo around the C. diphtheriae colonies. A low concentration of iron is required in the medium for toxin production. At high iron concentrations, iron molecules bind to an aporepressor on the beta bacteriophage, which carries the Tox gene. When bound to iron, the aporepressor shuts down toxin production (1).

The current definition of diphtheria used by the Centers for Disease Control and Prevention (CDC) is based on both laboratory and clinical criteria (3).

Laboratory:

Clinical:

Signs and Symptoms:

The symptoms of diphtheria usually begin two to seven days after infection. Symptoms of diphtheria include fever of 38°C (100.4°F) or above, chills, fatigue, bluish skin coloration, sore throat, hoarseness, cough, headache, difficulty swallowing, painful swallowing, difficulty breathing, rapid breathing, foul-smelling bloodstained nasal discharge and lymphadenopathy (4). Symptoms can also include cardiac arrhythmias, myocarditis, and cranial and peripheral nerve palsies (5).

Virulence Mechanisms:

Diphtheria toxin is produced by C. diphtheriae only when infected with a bacteriophage that integrates the toxin-encoding genetic elements into the bacteria (5).

Diphtheria toxin is a single, 60,000 molecular weight protein composed of two peptide chains, fragment A and fragment B, held together by a disulfide bond. Fragment B is a recognition subunit that gains the toxin entry into the host cell by binding to the EGF-like domain of heparin-binding EGF-like growth factor (HB-EGF) on the cell surface. This signals the cell to internalize the toxin within an endosome via receptor-mediated endocytosis. Inside the endosome, the toxin is split by a trypsin-like protease into its individual A and B fragments. The acidity of the endosome causes fragment B to create pores in the endosome membrane, thereby catalyzing the release of fragment A into the cell's cytoplasm (6).

Fragment A inhibits the synthesis of new proteins in the affected cell. It does this by catalyzing ADP-ribosylation of elongation factor EF-2—a protein that is essential to the translation step of protein synthesis. This ADP-ribosylation involves the transfer of an ADP-ribose from NAD+ to a diphthamide (a modified histidine) residue within the EF-2 protein. Since EF-2 is needed for the moving of tRNA from the A-site to the P-site of the ribosome during protein translation, ADP-ribosylation of EF-2 prevents protein synthesis (6).

Control/Treatment:

The disease may remain manageable, but in more severe cases, lymph nodes in the neck may swell, and breathing and swallowing will be more difficult. People in this stage should seek immediate medical attention, as obstruction in the throat may require intubation or a tracheotomy. Abnormal cardiac rhythms can occur early in the course of the illness or weeks later, and can lead to heart failure. Diphtheria can also cause paralysis in the eye, neck, throat, or respiratory muscles. Patients with severe cases will be put in a hospital intensive care unit and be 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 should not await laboratory confirmation (6).

Antibiotics have not been demonstrated to affect healing of local infection in diphtheria patients treated with antitoxin. Antibiotics are used in patients or carriers to eradicate C. diphtheriae and prevent its transmission to others. The CDC recommends (7) either:

In cases that progress beyond a throat infection, diphtheria toxin spreads through the blood and can lead to potentially life-threatening complications that affect other organs, such as the heart and kidneys. The toxin can cause damage to the heart that affects its ability to pump blood or the kidneys' ability to clear wastes. It can also cause nerve damage, eventually leading to paralysis. About 40% to 50% of those left untreated can die.

There are four combination vaccines that are used to prevent diptheria, tetanus and pertussis (DTP). They include DTaP, Tdap, DT, and Td. The upper and lowercase letter denote the strength of the doses while the “a” stands for “acellular.” Acellular means that only part of the B. pertussis is used to stimulate antibody production. Two, DTaP and DT, are given to younger children (under 7 years old) and two, Tdap and Td, are given to individuals7 years old and older. There are a series of 5 vaccination shots that should be administered at ages 2, 4, 6, 15-18 months old, and a final one between 4-6 years old (8).

Current Information:

Diphtheria is a serious disease, with fatality rates between 5% and 10%. In children under five years and adults over 40 years, the fatality rate may be as much as 20% (7). Outbreaks, though very rare, still occur worldwide, even in developed nations, such as Germany and Canada. 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. In 1991, there were 2,000 cases of diphtheria in the USSR. By 1998, according to Red Cross estimates, there were as many as 200,000 cases in the Commonwealth of Independent States, with 5,000 deaths (9). This was so great an increase that diphtheria was cited in the Guinness Book of World Records as "most resurgent disease" (10).

Diphtheria is a contagious disease spread by direct physical contact or breathing the aerosolized secretions of infected individuals. Historically quite common, diphtheria has largely been eradicated in industrialized nations through widespread vaccination. In the United States, for example, there were 53 reported cases of diphtheria between 1980 and 2000, but only a total of 2 cases of diphtheria have been reported in the 21st century, the last of which was in 2003 (6). The diphtheria–pertussistetanus (DPT) vaccine is recommended for all school-age children in the U.S., and boosters of the vaccine are recommended for adults, since the benefits of the vaccine decrease with age without constant re-exposure; they are particularly recommended for those traveling to areas where the disease has not been eradicated.

 Work cited:

1. Atkinson W, Hamborsky J, McIntyre L, Wolfe S, eds. (2007). Diphtheria. in: Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book) (10 ed.). Washington DC: Public Health Foundation. pp. 59–70.

2. Freeman VJ, Morse IU (1953). "FURTHER OBSERVATIONS ON THE CHANGE TO VIRULENCE OF BACTERIOPHAGE-INFECTED AVIRULENT STRAINS OF CORYNEBACTERIUM DIPHTHERIAE". Journal of Bacteriology 63 (3): 407–414. PMC 169283. PMID 14927573.

3. The first version of this article was adapted from the CDC document "Diphtheria - 1995 Case Definition" at http://www.cdc.gov/epo/dphsi/casedef/diphtheria_current.htm. As a work of an agency of the U.S. Government without any other copyright notice it should be available as a public domain resource.

4.Havaldar, PV; Sankpal MN, Doddannavar RP. (2000). "Diphtheritic myocarditis: clinical and laboratory parameters of prognosis and fatal outcome.". Annals of Tropical Paediatrics 20 (3): 209–15. PMID 11064774

5.Nester, Eugene W.; et al. (2004). Microbiology: A Human Perspective (Fourth ed.). Boston: McGraw-Hill. ISBN 0-07-247382-7.

6.Office of Laboratory Security, Public Health Agency of Canada Corynebacterium diphtheriae Material Safety Data Sheet. January 2000

7. "Preventing Tetanus, Diphtheria, and Pertussis Among Adolescents: Use of Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccines." MMWR. 24 March 2013. CDC. 3 May 2013  http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5503a1.htm

8.Solders, G; Nennesmo I, Persson A. (1989). "Diphtheritic neuropathy, an analysis based on muscle and nerve biopsy and repeated neurophysiological and autonomic function tests". J Neurol Neurosurg Psychiatry 52 (7): 876–80. doi:10.1136/jnnp.52.7.876. PMC 1031936. PMID 2549201.

9. "United States mortality rate from measles, scarlet fever, typhoid, whooping cough, and diphtheria from 1900–1965". HealthSentinel.com. Archived from the original on 2008-05-08. Retrieved 2008-06-30.

10. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002575/ May 6, 2013 10pm