[ The bacterium was identified in 1882 by Edwin Klebs.]
Signs and symptoms
The symptoms of diphtheria usually begin two to seven days after infection. They include fever of 38 °C (100.4 °F) or above; chills; fatigue; bluish skin coloration (cyanosis); sore throat; Dysphonia; cough; headache; difficulty swallowing; painful swallowing; difficulty breathing; rapid breathing; foul-smelling and bloodstained nasal discharge; and lymphadenopathy.
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,"
Transmission
Human-to-human transmission of diphtheria typically occurs through the air when an infected individual coughs or sneezes. Breathing in particles released from the infected individual leads to infection.[ Diphtheria Causes and Transmission . U.S. Center for Disease Control and Prevention (2016).] Contact with any lesions on the skin can also lead to transmission of diphtheria, but this case is uncommon.
Mechanism
Diphtheria toxin (DT) is produced only by C. diphtheriae infected with a certain type of bacteriophage.
The diphtheria toxin precursor is a protein of molecular mass 60 kDa. Certain proteases, such as trypsin, selectively cleave DT to generate two peptide chains, amino-terminal fragment A (DT-A) and carboxyl-terminal fragment B (DT-B), which are held together by a disulfide bond.
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
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Isolation of C. diphtheriae from a Gram stain or throat culture from a clinical specimen.
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Histopathologic diagnosis of diphtheria by Albert's stain.
Toxin demonstration
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In vivo tests (guinea pig inoculation): Subcutaneous and intracutaneous tests.
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In vitro test: Elek's gel precipitation test, detection of tox gene by PCR, ELISA, ICA.
Clinical criteria
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Upper respiratory tract illness with sore throat.
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Low-grade fever (above is rare).
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An adherent, dense, grey pseudomembrane covering the posterior aspect of the pharynx; in severe cases, it can extend to cover the entire tracheobronchial tree.
Case classification
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Probable: a clinically compatible case that is not laboratory-confirmed, and is not epidemiologically linked to a laboratory-confirmed case.
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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.
Prevention
Vaccination against diphtheria is commonly done in infants, and delivered as a combination vaccine, such as a DPT vaccine (diphtheria, pertussis, tetanus). Pentavalent vaccines, which vaccinate against diphtheria and four other childhood diseases simultaneously, are frequently used in disease prevention programs in developing countries by organizations such as UNICEF.
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 diphtheria antitoxin (consisting of antibodies isolated from the serum of horses that have been challenged with diphtheria toxin).
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 (CDC) recommends[The first version of this article was adapted from the Centers for Disease Control and Prevention document "Diphtheria ( Corynebacterium diphtheriae) 1995 Case Definition" . 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:
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Metronidazole
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Erythromycin is given (orally or by injection) for 14 days (40 mg/kg per day with a maximum of 2 g/d), or
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Procaine penicillin G is 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.
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. Damage to the heart caused by the toxin affects the heart's ability to pump blood, or the kidneys' ability to clear wastes. It can also cause nerve damage, eventually leading to paralysis. About 40–50% of those left untreated can die.
Epidemiology
for diphtheria per 100,000 inhabitants in 2004:
]]
between 1997 and 2006:
]]
Diphtheria is fatal in 5–10% of cases. In children under five years and adults over 40 years, the fatality rate may be as much as 20%.
History
In 1613, Spain experienced an epidemic of diphtheria, referred to as El Año de los Garrotillos (The Year of Strangulations).
In 1705, the Mariana Islands experienced an epidemic of diphtheria and typhus simultaneously, reducing the population to about 5,000 people.
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 the illness had spread from France. In 1826, Pierre Bretonneau gave the disease the name diphthérite (from Greek διφθέρα, diphthera 'leather'), describing the appearance of pseudomembrane in the throat.[Bretonneau, Pierre (1826) Des inflammations spéciales du tissu muqueux, et en particulier de la diphtérite, ou inflammation pelliculaire, connue sous le nom de croup, d'angine maligne, d'angine gangréneuse, etc. Special Paris, France: Crevot.]
A condensed version of this work is available in: P. Bretonneau (1826) "Extrait du traité de la diphthérite, angine maligne, ou croup épidémique" (Extract from the treatise on diphtheria, malignant throat infection, or epidemic croup), Archives générales de médecine, series 1, 11 : 219–254. From p. 230: " … M. Bretonneau a cru convenable de l'appeler diphthérite, dérivé de ΔΙΦθΕΡΑ, … " ( … Mr. Bretonneau thought it appropriate to call it diphtheria, derived from ΔΙΦθΕΡΑ diphthera, … )
In 1856, Victor Fourgeaud described an epidemic of diphtheria in California.
In 1878, Princess Alice (Queen Victoria's second daughter) and her family became infected with diphtheria; Princess Alice and her four-year-old daughter, Princess Marie, both died.
In 1883, Edwin Klebs identified the bacterium causing diphtheria,[Klebs, E. (1883) "III. Sitzung: Ueber Diphtherie" (Third session: On diphtheria), Verhandlungen des Congresses für innere Medicin. Zweiter Congress gehalten zu Wiesbaden, 18.-23. April 1883 (Proceedings of the Congress on Internal Medicine. Second congress held at Wiesbaden, 18–23 April 1883), 2 : 139–154.] and named it Klebs–Loeffler bacterium. The club shape of this bacterium helped Edwin to differentiate it from other bacteria. Over time, it has been called Microsporon diphtheriticum, Bacillus diphtheriae, and Mycobacterium diphtheriae. Current nomenclature is Corynebacterium diphtheriae.
In 1884, German bacteriologist Friedrich Loeffler became the first person to cultivate C. diphtheriae.[Loeffler, F. (1884) "Untersuchungen über die Bedeutung der Mikroorganismen für die Entstehung der Diphtherie, beim Menschen, bei der Taube und beim Kalbe" (Investigations into the significance of microorganisms in the development of diphtheria among humans, pigeons, and calves), Mitteilungen aus der Kaiserlichen Gesundheitsamte (Communications from the Imperial Office of Health), 2 : 421–499.] He used Koch's postulates to prove association between C. diphtheriae and diphtheria. He also showed that the bacillus produces an exotoxin.
In 1885, Joseph P. O'Dwyer introduced the O'Dwyer tube for laryngeal intubation in patients with an obstructed larynx. It soon replaced Tracheotomy 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.[Roux, E. and Yersin, A. (December 1888) "Contribution à l'étude de la diphthérte" (Contribution to the study of diphtheria), Annales de l'Institute Pasteur, 2 : 629–661.]
In 1890, Shibasaburō Kitasato and Emil von Behring immunized guinea pigs with heat-treated diphtheria toxin.[Behring, E. and Kitasato, S. (1890) "Ueber das Zustandekommen der Diphtherie-Immunitat und der Tetanus-Immunitat bei Thieren" (On the realization of diphtheria immunity and tetanus immunity among animals), Deutsche medizinsche Wochenschrift, 16 : 1113–1114.] They also immunized goats and horses in the same way, and showed that an "antitoxin" made from serum of immunized animals could cure the disease in non-immunized animals. Behring used this antitoxin (now known to consist of Antibody that neutralize the toxin produced by C. diphtheriae) for human trials in 1891, but they were unsuccessful. Successful treatment of human patients with horse-derived antitoxin began in 1894, after production and quantification of antitoxin had been optimized.[Emil von Behring Serum Therapy in Therapeutics and Medical Science. Nobel Lecture, 12 December 1901. nobelprize.org]
In 1895, H. K. Mulford Company of Philadelphia started production and testing of diphtheria antitoxin in the United States.
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,
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.
In 1905, Franklin Royer, from Philadelphia's Municipal Hospital, published a paper urging timely treatment for diphtheria and adequate doses of 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 had not been exposed to diphtheria were 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 significantly in 1924.
In 1919, in Dallas, 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. The manufacturer of the antitoxin, the Mulford Company of Philadelphia, paid damages in every case.
During the 1920s, an annual estimate of 100,000 to 200,000 diphtheria cases and 13,000 to 15,000 deaths occurred in the United States.
In 1926, Alexander Thomas Glenny increased the effectiveness of diphtheria toxoid (a modified version of the toxin used for vaccination) by treating it with aluminum salts.[ Immunology and Vaccine-Preventable Diseases – Pink Book – Diphtheria, CDC] In 1939, Dr. Nora Wattie, who was the Principal Medical Officer (Maternity and Child Welfare) of Glasgow between 1934– 1964,
Widespread vaccination pushed cases in the United States down from 4.4 per 100,000 inhabitants in 1932 to 2.0 in 1937. In Nazi Germany, where authorities preferred treatment and isolation over vaccination (until about 1939–1941), cases rose over the same period from 6.1 to 9.6 per 100,000 inhabitants.
Between June 1942 and February 1943, 714 cases of diphtheria were recorded at Sham Shui Po Barracks, resulting in 112 deaths because the Imperial Japanese Army did not release supplies of anti-diphtheria serum.
In 1943, diphtheria outbreaks accompanied war and disruption in Europe. The 1 million cases in Europe resulted in 50,000 deaths.
During 1948 in Kyoto, 68 of 606 children died after diphtheria immunization due to improper manufacture of aluminum phosphate toxoid.
In 1974, the World Health Organization included DPT vaccine in their Expanded Programme on Immunization for developing countries.
In 1975, an outbreak of cutaneous diphtheria in Seattle, was reported.
After the breakup of the former Soviet Union in 1991, 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. Between 1991 and 1998, as many as 200,000 cases were reported in the Commonwealth of Independent States, and resulted in 5,000 deaths.[
]
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 six-year-old child who died of the illness had not been previously vaccinated due to parental opposition to vaccination.
In March 2016, a three-year-old girl died of diphtheria in the University Hospital of Antwerp, Belgium.
In June 2016, a three-year-old, five-year-old, and seven-year-old girl died of diphtheria in Kedah, Malacca, and Sabah, Malaysia.
In January 2017, more than 300 cases were recorded in Venezuela.
In 2017, outbreaks occurred in a Rohingya refugee camp in Bangladesh, and amongst children unvaccinated due to the Yemeni Civil War.[ Diphtheria: What Exactly Is It ... And Why Is It Back?]
In November and December 2017, an outbreak of diphtheria occurred in Indonesia, with more than 600 cases found and 38 fatalities.
In November 2019, two cases of diphtheria occurred in the Lothian area of Scotland.
In July 2022, two cases of diphtheria occurred in northern New South Wales, Australia.
In October 2022, there was an outbreak of diphtheria at the former RAF Manston, a former Ministry of Defence (MoD) site in Kent, England, which had been converted to an asylum seeker processing centre. The capacity of the processing centre was 1,000 people, although about 3,000 were living at the site, with some accommodated in tents. The Home Office, the government department responsible for asylum seekers, refused to confirm the number of cases.
In December 2023 there was an outbreak at a school in Luton, in the United Kingdom. UK Health Security Agency (UKHSA) issued a statement saying specialists have been providing public health support following confirmation of the diphtheria case at a primary school in Luton. The agency said it is working closely with local and national partners "to ensure all necessary public health measures are implemented" following the discovery of the new case. The statement added: "We have conducted a risk assessment and close contacts of the case have been identified and where appropriate, vaccination and advice will be given to prevent the spread of the infection."
Further reading
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Hammonds, Evelynn Maxine. Childhood's Deadly Scourge: The Campaign to Control Diphtheria in New York City, 1880-1930 (1999)
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Hammonds, Evelynn Maxine. "The search for perfect control: A social history of diphtheria, 1880-1930" (PhD dissertation, Harvard University; ProQuest Dissertations & Theses, 1993. 9318671).
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"Antitoxin dars 1735 and 1740." The William and Mary Quarterly, 3rd Ser., Vol 6, No 2. p. 338.
External links
