Diphtheria

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Diphtheria ( Greek language|Greek d?f???a ( diphthera ) "pair of leather scrolls") is an upper Respiration (physiology)|respiratory tract illness caused by Corynebacterium diphtheriae , a Facultative anaerobic organism|facultative anaerobic , Gram-positive bacterium .Office of Laboratory Security, Public Health Agency of Canada Material Safety Data Sheet. January 2000.Corynebacterium diphtheriae only produces diphtheria toxin when lysogenized by beta phage It is characterized by sore throat, low fever , and an adherent membrane (a pseudomembrane ) on the tonsil s, pharynx , and/or nasal cavity. A milder form of diphtheria can be restricted to the skin. Less common consequences include myocarditis (about 20% of cases) and peripheral neuropathy (about 10% of cases).

Diphtheria is a contagious disease spread by direct physical contact or breathing the particulate|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 52 reported cases of diphtheria between 1980 and 2000; between 2000 and 2007, there were only three cases as the diphtheria– pertussis – tetanus DPT vaccine|(DPT) vaccine is recommended for all school-age children. 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.

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 (medical)|fatigue , bluish skin coloration, sore throat, hoarseness, cough, headache, difficulty swallowing, painful swallowing, difficulty breathing, rapid breathing, foul-smelling bloodstained nasal discharge and lymphadenopathy . http://www.nhs.uk/Conditions/Diphtheria/Pages/Symptoms.aspx http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002575/ Symptoms can also include cardiac arrhythmias, myocarditis, and cranial and peripheral nerve palsies.

Diphtheria toxin mechanism

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

Diphtheria toxin is a single, 60,000 molecular mass|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 .

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.

ADP-ribosylation of EF-2 is reversed by giving high doses of nicotinamide (a form of vitamin B₃), since this is one of the reaction's end-products, and high amounts will drive the reaction in the opposite direction.

Diagnosis

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

Laboratory criteria

Isolation of Corynebacterium diphtheriae from a gram stain or throat culture from a clinical specimen http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002575/, or

Histopathologic diagnosis of diphtheria

Clinical criteria

Upper respiratory tract illness with sore throat

Low-grade fever (> is rare)

An adherent pseudomembrane of the tonsil(s), pharynx, and/or nose.

Case classification

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

Empirical treatment should generally be started in a patient in whom suspicion of diphtheria is high.

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.

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 The first version of this article was adapted from the Centers for Disease Control and Prevention|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 . either:

Metronidazole

Erythromycin (orally or by injection) for 14 days (40& nbsp;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 patients weighing <10& nbsp;kg and 600,000 U/d for those weighing >10& nbsp;kg). Patients with allergies to penicillin G or erythromycin can use rifampin or clindamycin .

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.

Epidemiology

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%. 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. This was so great an increase that diphtheria was cited in the Guinness Book of World Records as "most resurgent disease".

History

The disease was named by French doctor Pierre Bretonneau in 1855 (substituted for his earlier term diphthérite ).

In 1878, Queen Victoria of the United Kingdom|Queen Victoria's daughter Princess Alice of the United Kingdom|Princess Alice and her family became infected with it, causing two deaths, Princess Marie of Hesse and by Rhine and Princess Alice herself.

In the 1920s, there were an estimated 100,000 to 200,000 cases of diphtheria per year in the United States, causing 13,000 to 15,000 deaths per year. Children represented a large majority of these cases and fatalities. One of the most famous outbreaks of diphtheria was in Nome, Alaska ; the 1925 serum run to Nome|"Great Race of Mercy" to deliver diphtheria antitoxin is now celebrated by the Iditarod Trail Sled Dog Race .

One of the first effective treatments for diphtheria was discovered in the 1880s by U.S. physician Joseph O'Dwyer (1841–1898). O'Dwyer developed intubation|tubes that were inserted into the throat, and prevented victims from suffocating due to the membrane sheath that grows over and obstructs airways. In 1884, Friedrich Loeffler discovered the causative organism ( Corynebacterium diphtheriae ). In December 1890, the German physician Emil von Behring developed an antitoxin that did not kill the bacterium, but neutralized the toxic poisons the bacterium releases into the body. Von Behring discovered that animal blood has antitoxins in it, so he took the blood, removed the clotting agents and injected it into human patients. "The paper shook the scientific world. Work on diphtheria at a level of intensity heretofore unknown proceeded in laboratories. Over the Christmas holiday in 1891 in Berlin, the first attempt to cure a person of diphtheria was made. It succeeded. . . . It was the first cure ." John M. Barry, The Great Influenza; The Story of the Deadliest Pandemic in History (New York: Penguin Books, c2004, 2005) p. 70. Von Behring was awarded the first Nobel Prize in Medicine for his role in the discovery, and development of a serum therapy for diphtheria. (Americans William H. Park and Anna Wessels Williams , and Pasteur Institute scientists Emile Roux and Auguste Chaillou also independently developed diphtheria antitoxin in the 1890s.) The first successful vaccine for diphtheria was developed in 1913 by Behring. However, antibiotics against diphtheria were not available until the discovery and development of sulfa drugs .

The Schick test , invented between 1910 and 1911, is a test used to determine whether or not a person is susceptible to diphtheria. It was named after its inventor, Béla Schick (1877–1967), a Hungarian-born American pediatrician. A massive five-year campaign was coordinated by Dr. Schick. As a part of the campaign, 85 million pieces of literature were distributed by the Metropolitan Life Insurance Company with an appeal to parents to "Save your child from diphtheria." A vaccine was developed in the next decade, and deaths began declining in earnest in 1924.

In early May 2010, a case of diphtheria was diagnosed in Port-au-Prince , Haiti after the devastating 2010 Haiti earthquake . The 15-year-old male patient died while workers searched for antitoxin.

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