Diphtheria
Overview
 
Diphtheria is an upper respiratory
Respiration (physiology)
'In physiology, respiration is defined as the transport of oxygen from the outside air to the cells within tissues, and the transport of carbon dioxide in the opposite direction...

 tract illness caused by Corynebacterium diphtheriae
Corynebacterium diphtheriae
Corynebacterium diphtheriae is a pathogenic bacterium that causes diphtheria. It is also known as the Klebs-Löffler bacillus, because it was discovered in 1884 by German bacteriologists Edwin Klebs and Friedrich Löffler .-Classification:Four subspecies are recognized: C. diphtheriae mitis, C....

, a facultative anaerobic
Facultative anaerobic organism
A facultative anaerobic organism is an organism, usually a bacterium, that makes ATP by aerobic respiration if oxygen is present but is also capable of switching to fermentation...

, Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...

 bacterium. It is characterized by sore throat, low fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

, and an adherent membrane (a pseudomembrane) on the tonsil
Tonsil
Palatine tonsils, occasionally called the faucial tonsils, are the tonsils that can be seen on the left and right sides at the back of the throat....

s, pharynx
Pharynx
The human pharynx is the part of the throat situated immediately posterior to the mouth and nasal cavity, and anterior to the esophagus and larynx. The human pharynx is conventionally divided into three sections: the nasopharynx , the oropharynx , and the laryngopharynx...

, and/or nasal cavity. A milder form of diphtheria can be restricted to the skin. Less common consequences include myocarditis
Myocarditis
Myocarditis is inflammation of heart muscle . It resembles a heart attack but coronary arteries are not blocked.Myocarditis is most often due to infection by common viruses, such as parvovirus B19, less commonly non-viral pathogens such as Borrelia burgdorferi or Trypanosoma cruzi, or as a...

 (about 20% of cases) and peripheral neuropathy (about 10% of cases).

Diphtheria is a contagious disease spread by direct physical contact or breathing the aerosolized secretions of infected individuals.
Unanswered Questions
Encyclopedia
Diphtheria is an upper respiratory
Respiration (physiology)
'In physiology, respiration is defined as the transport of oxygen from the outside air to the cells within tissues, and the transport of carbon dioxide in the opposite direction...

 tract illness caused by Corynebacterium diphtheriae
Corynebacterium diphtheriae
Corynebacterium diphtheriae is a pathogenic bacterium that causes diphtheria. It is also known as the Klebs-Löffler bacillus, because it was discovered in 1884 by German bacteriologists Edwin Klebs and Friedrich Löffler .-Classification:Four subspecies are recognized: C. diphtheriae mitis, C....

, a facultative anaerobic
Facultative anaerobic organism
A facultative anaerobic organism is an organism, usually a bacterium, that makes ATP by aerobic respiration if oxygen is present but is also capable of switching to fermentation...

, Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...

 bacterium. It is characterized by sore throat, low fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

, and an adherent membrane (a pseudomembrane) on the tonsil
Tonsil
Palatine tonsils, occasionally called the faucial tonsils, are the tonsils that can be seen on the left and right sides at the back of the throat....

s, pharynx
Pharynx
The human pharynx is the part of the throat situated immediately posterior to the mouth and nasal cavity, and anterior to the esophagus and larynx. The human pharynx is conventionally divided into three sections: the nasopharynx , the oropharynx , and the laryngopharynx...

, and/or nasal cavity. A milder form of diphtheria can be restricted to the skin. Less common consequences include myocarditis
Myocarditis
Myocarditis is inflammation of heart muscle . It resembles a heart attack but coronary arteries are not blocked.Myocarditis is most often due to infection by common viruses, such as parvovirus B19, less commonly non-viral pathogens such as Borrelia burgdorferi or Trypanosoma cruzi, or as a...

 (about 20% of cases) and peripheral neuropathy (about 10% of cases).

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
Vaccination
Vaccination is the administration of antigenic material to stimulate the immune system of an individual to develop adaptive immunity to a disease. Vaccines can prevent or ameliorate the effects of infection by many pathogens...

. In the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

, 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
Pertussis
Pertussis, also known as whooping cough , is a highly contagious bacterial disease caused by Bordetella pertussis. Symptoms are initially mild, and then develop into severe coughing fits, which produce the namesake high-pitched "whoop" sound in infected babies and children when they inhale air...

tetanus
Tetanus
Tetanus is a medical condition characterized by a prolonged contraction of skeletal muscle fibers. The primary symptoms are caused by tetanospasmin, a neurotoxin produced by the Gram-positive, rod-shaped, obligate anaerobic bacterium Clostridium tetani...

 (DPT) vaccine
DPT vaccine
DPT refers to a class of combination vaccines against three infectious diseases in humans: diphtheria, pertussis and tetanus...

 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.

Diphtheria toxin mechanism

Diphtheria toxin is produced by C. diphtheriae only when it is infected with a bacteriophage
Bacteriophage
A bacteriophage is any one of a number of viruses that infect bacteria. They do this by injecting genetic material, which they carry enclosed in an outer protein capsid...

 that integrates the toxin-encoding genetic elements into the bacteria.
Diphtheria toxin
Diphtheria toxin
Diphtheria toxin is an exotoxin secreted by Corynebacterium diphtheriae, the pathogen bacterium that causes diphtheria. Unusually, the toxin gene is encoded by a bacteriophage...

 is a single, 60,000 molecular weight
Molecular mass
The molecular mass of a substance is the mass of one molecule of that substance, in unified atomic mass unit u...

  protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 composed of two peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

 chains, fragment A and fragment B, held together by a disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...

. 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
Heparin-binding EGF-like growth factor
Heparin-binding EGF-like growth factor is a member of the EGF family of proteins. It has been shown to play a role in wound healing, cardiac hypertrophy and heart development and function.-Interactions:...

 (HB-EGF) on the cell surface. This signals the cell to internalize the toxin within an endosome
Endosome
In biology, an endosome is a membrane-bound compartment inside eukaryotic cells. It is a compartment of the endocytic membrane transport pathway from the plasma membrane to the lysosome. Molecules internalized from the plasma membrane can follow this pathway all the way to lysosomes for...

 via receptor-mediated endocytosis
Receptor-mediated endocytosis
Receptor-mediated endocytosis , also called clathrin-dependent endocytosis, is a process by which cells internalize molecules by the inward budding of plasma membrane vesicles containing proteins with receptor sites specific to the molecules being internalized.-Process:After the binding of a...

. Inside the endosome, the toxin is split by a trypsin-like protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....

 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 fragment A into the cell's cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...

.

Fragment A inhibits the synthesis of new proteins in the affected cell. It does this by catalyzing ADP-ribosylation
ADP-ribosylation
ADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein. These reactions are involved in cell signaling and the control of many cell processes, including DNA repair and apoptosis.-ADP-ribosylation enzymes:...

 of elongation factor
Elongation factor
Elongation factors are a set of proteins that facilitate the events of translational elongation, the steps in protein synthesis from the formation of the first peptide bond to the formation of the last one.Elongation is the most rapid step in translation:...

 EF-2—a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 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
Diphthamide
Diphthamide is a modified histidine amino acid found in eukaryotic elongation factor 2 .It is usually found at position H715 in mammalian eEF2 . This residue is modified by the protein encoded by the OVCA1 gene . DPH1 knockout mice are inviable while heterozygotes develop diverse types of...

 (a modified histidine
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...

) 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
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....

 during protein translation, ADP-ribosylation of EF-2 prevents protein synthesis.

ADP-ribosylation of EF-2 is reversed by giving high doses of nicotinamide
Nicotinamide
Nicotinamide, also known as niacinamide and nicotinic acid amide, is the amide of nicotinic acid . Nicotinamide is a water-soluble vitamin and is part of the vitamin B group...

 (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.

Transmission

Diphtheria pathogenesis most often occurs due to respiratory or skin transmission, which later develops into tissue necrosis, which is mediated by its toxin.

Diagnosis

The current definition of diphtheria used by the Centers for Disease Control and Prevention
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...

 (CDC) is based on both laboratory and clinical criteria.

Laboratory criteria

  • Isolation of Corynebacterium diphtheriae
    Corynebacterium diphtheriae
    Corynebacterium diphtheriae is a pathogenic bacterium that causes diphtheria. It is also known as the Klebs-Löffler bacillus, because it was discovered in 1884 by German bacteriologists Edwin Klebs and Friedrich Löffler .-Classification:Four subspecies are recognized: C. diphtheriae mitis, C....

    from a clinical specimen, or
  • Histopathologic diagnosis of diphtheria

Clinical criteria

  • Upper respiratory tract illness with sore throat
  • Low-grade fever (>103°F 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
Intubation
Tracheal intubation, usually simply referred to as intubation, is the placement of a flexible plastic or rubber tube into the trachea to maintain an open airway or to serve as a conduit through which to administer certain drugs...

 or a tracheotomy
Tracheotomy
Among the oldest described surgical procedures, tracheotomy consists of making an incision on the anterior aspect of the neck and opening a direct airway through an incision in the trachea...

. 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
Intensive Care Unit
thumb|220px|ICU roomAn intensive-care unit , critical-care unit , intensive-therapy unit/intensive-treatment unit is a specialized department in a hospital that provides intensive-care medicine...

 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 either:
  • Metronidazole
    Metronidazole
    Metronidazole is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal....

  • Erythromycin
    Erythromycin
    Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...

     (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 patients weighing <10 kg and 600,000 U/d for those weighing >10 kg). Patients with allergies to penicillin G or erythromycin can use rifampin or clindamycin
    Clindamycin
    Clindamycin rINN is a lincosamide antibiotic. It is usually used to treat infections with anaerobic bacteria but can also be used to treat some protozoal diseases, such as malaria...

    .


In cases that progress beyond a throat infection, diphtheria toxin spreads through the bloodstream and can lead to potentially life-threatening complications that affect other organs of the body, 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
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...

 and Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...

. After the breakup of the former Soviet Union
Soviet Union
The Soviet Union , officially the Union of Soviet Socialist Republics , was a constitutionally socialist state that existed in Eurasia between 1922 and 1991....

 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
Commonwealth of Independent States
The Commonwealth of Independent States is a regional organization whose participating countries are former Soviet Republics, formed during the breakup of the Soviet Union....

, 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

In 1878, Queen Victoria's daughter Princess Alice
Princess Alice of the United Kingdom
The Princess Alice was a member of the British royal family, the third child and second daughter of Queen Victoria and Prince Albert of Saxe-Coburg and Gotha.Alice's education was devised by Albert's close friend and adviser, Baron Stockmar...

 and her family became infected with it, causing two deaths, Princess Marie of Hesse and by Rhine
Princess Marie of Hesse and by Rhine
Princess Marie of Hesse and by Rhine , , was the youngest daughter of Princess Alice of the United Kingdom and Ludwig IV, the Grand Duke of Hesse. Her mother was the second daughter of Queen Victoria and Prince Albert of Saxe-Coburg-Gotha...

 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
Nome, Alaska
Nome is a city in the Nome Census Area in the Unorganized Borough of the U.S. state of Alaska, located on the southern Seward Peninsula coast on Norton Sound of the Bering Sea. According to the 2010 Census, the city population was 3,598. Nome was incorporated on April 9, 1901, and was once the...

; the "Great Race of Mercy"
1925 serum run to Nome
During the 1925 serum run to Nome, also known as the "Great Race of Mercy," 20 mushers and about 150 sled dogs relayed diphtheria antitoxin by dog sled across the U.S. territory of Alaska in a record-breaking five and a half days, saving the small city of Nome and the surrounding communities from...

 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
Joseph O'Dwyer
Joseph O'Dwyer was a Catholic American physician. He discovered a valuable system of intubation in diphtheria cases.-External links:* From the 1910...

 (1841–1898). O'Dwyer developed tubes
Intubation
Tracheal intubation, usually simply referred to as intubation, is the placement of a flexible plastic or rubber tube into the trachea to maintain an open airway or to serve as a conduit through which to administer certain drugs...

 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 the 1890s, 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. Von Behring was awarded the first Nobel Prize
Nobel Prize
The Nobel Prizes are annual international awards bestowed by Scandinavian committees in recognition of cultural and scientific advances. The will of the Swedish chemist Alfred Nobel, the inventor of dynamite, established the prizes in 1895...

 in Medicine for his role in the discovery, and development of a serum therapy for diphtheria. (Americans William H. Park and Anna Wessels Williams
Anna Wessels Williams
Dr. Anna Wessels Williams worked as a bacteriologist at the first municipal diagnostic laboratory in the United States, helped develop the diphtheria antitoxin and was the first woman to be elected chair of the laboratory section of the American Public Health Association.- Overview :Anna Wessels...

, and Pasteur Institute
Pasteur Institute
The Pasteur Institute is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who made some of the greatest breakthroughs in modern medicine at the time, including pasteurization and vaccines for anthrax...

 scientists Emile Roux and Auguste Chaillou
Auguste Chaillou
Auguste Chaillou was a French biologist and physician born in Parennes in the department of Sarthe. He worked at the Hôpital des Enfants-Malades, and for most of his career was associated with the Pasteur Institute in Paris.Chaillou is best-known for his development of the anti-diphtheria serum...

 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
Schick test
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 , a Hungarian-born American pediatrician....

, 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
Béla Schick
Béla Schick , was a Hungarian-born American pediatrician. He is the founder of the Schick test. Was born in Balatonboglár, Hungary, and brought up in Graz, Austria, where he attended medical school. In 1902 he joined the Medicine Faculty of the University of Viennawhere he remained until 1923...

 (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
Metropolitan Life Insurance Company
MetLife, Inc. is the holding corporation for the Metropolitan Life Insurance Company, or MetLife, for short, and its affiliates. MetLife is among the largest global providers of insurance, annuities, and employee benefit programs, with 90 million customers in over 60 countries...

 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
Port-au-Prince
Port-au-Prince is the capital and largest city of the Caribbean nation of Haiti. The city's population was 704,776 as of the 2003 census, and was officially estimated to have reached 897,859 in 2009....

, Haiti
Haiti
Haiti , officially the Republic of Haiti , is a Caribbean country. It occupies the western, smaller portion of the island of Hispaniola, in the Greater Antillean archipelago, which it shares with the Dominican Republic. Ayiti was the indigenous Taíno or Amerindian name for the island...

 after the devastating 2010 Haiti earthquake
2010 Haiti earthquake
The 2010 Haiti earthquake was a catastrophic magnitude 7.0 Mw earthquake, with an epicentre near the town of Léogâne, approximately west of Port-au-Prince, Haiti's capital. The earthquake occurred at 16:53 local time on Tuesday, 12 January 2010.By 24 January, at least 52 aftershocks...

. The 15-year-old male patient died while workers searched for antitoxin.

Further reading

  • "Antitoxin dars 1735 and 1740." The William and Mary Quarterly, 3rd Ser., Vol 6, No 2. p. 338.
The source of this article is wikipedia, the free encyclopedia.  The text of this article is licensed under the GFDL.
 
x
OK