Diphtheria

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 (cyanosis), sore throat, hoarseness, cough, headache, difficulty swallowing, painful swallowing, difficulty breathing, rapid breathing, foul-smelling and bloodstained nasal discharge, and lymphadenopathy. Symptoms can also include cardiac arrhythmias, myocarditis, and cranial and peripheral nerve palsies.

Diphtheritic croup

Laryngeal diphtheria can lead to a characteristic swollen neck and throat, or "bull neck". The swollen throat is often accompanied by a serious respiratory condition, characterized by a brassy or "barking" cough, stridor, hoarseness, and difficulty breathing, and historically referred to variously as "diphtheritic croup", "true croup", or sometimes simply as "croup". Diphtheritic croup is extremely rare in countries where diphtheria vaccination is customary. As a result, the term "croup" nowadays most often refers to an unrelated viral illness that produces similar but milder respiratory symptoms.

Transmission

Human to human transmission of diphtheria typically occurs through the air when an infected individual coughs or sneezes. Breathing in of particles released from the infected individual leads to infection Contact with any lesions on the skin can also lead to transmission, but it is uncommon. Indirect infections can occur, as well, if an infected individual touches a surface or object. The bacteria can be left behind and still remain viable until an uninfected individual touches the same surface or object. Also, some evidence indicates diphtheria has the potential to be zoonotic, but this has yet to be confirmed. Corynebacterium ulcerans has been found in some animals, which would suggest zoonotic potential

Mechanism

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

Diphtheria toxin is a single, 60-kDa-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 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 catalysing the release of fragment A into the cell's cytoplasm.

Fragment A inhibits the synthesis of new proteins in the affected cell 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 drive the reaction in the opposite direction.

Diagnosis

The current clinical case definition of diphtheria used by the United States' Centers for Disease Control and Prevention is based on both laboratory and clinical criteria.

Laboratory criteria

Clinical criteria

Case classification

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

Prevention

Quinvaxem is a widely administered pentavalent vaccine, which is a combination of five vaccines in one that protect infantile children from diphtheria, among other common child diseases. Diphtheria vaccine is usually combined at least with tetanus (Td) and often with pertussis (DTP, DTaP, TdaP) vaccines, as well.

Treatment

The disease may remain manageable, but in more severe cases, lymph nodes in the neck may swell, and breathing and swallowing are 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 are put in a hospital intensive care unit 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 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 Centers for Disease Control and Prevention recommends 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.

Epidemiology

Diphtheria is fatal in between 5% and 10% of cases. In children under five years and adults over 40 years, the fatality rate may be as much as 20%. In 2013, it resulted in 3,300 deaths, down from 8,000 deaths in 1990.

Outbreaks, though very rare, still occur worldwide, including in developed nations, such as Germany among unvaccinated children, and Canada^{needs citation}. After the breakup of the former Soviet Union in the early 1990s, vaccination rates in its constituent countries fell so low that an explosion of diphtheria cases occurred. In 1991, 2,000 cases of diphtheria occurred in the USSR. By 1998, according to Red Cross estimates, as many as 200,000 cases in the Commonwealth of Independent States were reported, with 5,000 deaths.

History

In 1613, Spain experienced an epidemic of diphtheria. The year is known as El Año de los Garrotillos (The Year of Strangulations) in the history of Spain.

In 1735, a diphtheria epidemic swept through New England.

Before 1826, diphtheria was known by different names across the world. In England, it was known as Boulogne sore throat, as it spread from France. In 1826, Pierre Bretonneau gave the disease the name diphthérite (from Greek diphthera "leather") describing the appearance of pseudomembrane in the throat.

In 1856, Victor Fourgeaud described an epidemic of diphtheria in California.

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

In 1883, Edwin Klebs identified the bacterium and named it Klebs-Loeffler bacterium. The club shape of bacterium helped Edwin to differentiate it from other bacteria. Over the period of time, it was called Microsporon diphtheriticum, Bacillus diphtheriae, and Mycobacterium diphtheriae. Current nomenclature is Corynebacterium diphtheriae.

Friedrich Loeffler was the first one to cultivate C. diphtheriae in 1884. He used Koch's postulates to prove association between C. diphtheriae and diphtheria. He also showed that the bacillus produces an exotoxin.

Joseph P. O’Dwyer introduced the O'Dwyer tube for laryngeal intubation in patients with an obstructed larynx in 1885. It soon replaced tracheostomy as the emergency diphtheric intubation method.

In 1888, Emile Roux and Alexandre Yersin showed that a substance produced by C. diphtheriae caused symptoms of diphtheria in animals.

In 1890, Shibasaburo Kitasato and Emil von Behring immunized guinea pigs with heat-treated diphtheria toxin. The first cure of a person with diphtheria is dated to the 1891 Christmas holiday in Berlin. Von Behring won the first Nobel Prize in medicine in 1901 for his work on diphtheria.

In 1895, H. K. Mulford Company of Philadelphia started production and testing of diphtheria antitoxin in the United States. Park and Biggs described the method for producing serum from horses for use in diphtheria treatment.

In 1897, Paul Ehrlich developed a standardized unit of measure for diphtheria antitoxin. This was the first ever standardization of a biological product, and played an important role in future developmental work on sera and vaccines.

In 1901, 10 of 11 inoculated St. Louis children died from contaminated diphtheria antitoxin. The horse from which the antitoxin was derived died of tetanus. This incident, coupled with a tetanus outbreak in Camden, New Jersey, played an important part in initiating federal regulation of biologic products.

On 7 January 1904, Ruth Cleveland died of diphtheria at the age of 12 years in Princeton, New Jersey. Ruth was the eldest daughter of former President Grover Cleveland and the former first lady Frances Folsom. She was the only one of the Clevelands' five children who died before adulthood.

In 1905, Franklin Royer, from Philadelphia's Municipal Hospital, published a paper urging timely treatment for diphtheria and adequate doses of antitoxin. In the same year, Clemens Pirquet and Bela Schick described serum sickness in children receiving large quantities of horse-derived antitoxin.

Between 1910 and 1911, Béla Schick developed the Schick test to detect pre-existing immunity to diphtheria in an exposed person. Only those who were not exposed to diphtheria were preferably vaccinated. 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 1919, in Dallas, Texas, 10 children were killed and 60 others made seriously ill by toxic antitoxin which had passed the tests of the New York State Health Department. Mulford Company of Philadelphia (manufacturers) paid damages in every case.

In the 1920s, an estimated 100,000 to 200,000 cases of diphtheria occurred 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 infamous outbreaks of diphtheria was in Nome, Alaska; the "Great Race of Mercy" to deliver diphtheria antitoxin is now celebrated by the Iditarod Trail Sled Dog Race.

In 1926, Alexander Thomas Glenny increased the effectiveness of diphtheria toxoid by treating it with aluminum salts.

In 1943, diphtheria outbreaks accompanied war and disruption in Europe. The 1 million cases in Europe resulted in 50,000 deaths.

In 1949, 68 of 606 children died after diphtheria immunization due to improper manufacture of aluminum phosphate toxoid.

In 1974, World Health Organization included DPT vaccine in their Expanded Programme on Immunization for developing countries.

In 1975, an outbreak of cutaneous diphtheria in Seattle, Washington, was reported .

In 1994, the Russian Federation had 39,703 diphtheria cases. In contrast, in 1990, only 1,211 cases were reported.

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.

In 2013, three children died of diphtheria in Hyderabad, India.

In early June 2015, a case of diphtheria was diagnosed at Vall d'Hebron University Hospital in Barcelona, Spain. The 6-year-old child who died of the illness had not been previously vaccinated due to parental opposition to vaccination. It was the first case of diphtheria in the country since 1986 as reported by "El Mundo" or from 1998, as reported by WHO.

In March 2016, a 3-year-old girl died of diphtheria in the University Hospital of Antwerp, Belgium.

In June 2016, three cases of a 3-year-old, 5-year-old, and 7-year-old girl died of diphtheria in Kedah and Malacca, Sabah Malaysia.