Diphtheria is usually spread between people by direct contact or through the air. It may also be spread by contaminated objects. Some people carry the bacterium without having symptoms, but can still spread the disease to others. The three main types of C. diphtheriae cause different severities of disease. The symptoms are due to a toxin produced by the bacterium. Diagnosis can often be made based on the appearance of the throat with confirmation by microbiological culture. Previous infection may not protect against future infection.
In 2015, 4,500 cases were officially reported worldwide, down from nearly 100,000 in 1980. About a million cases a year are believed to have occurred before the 1980s. Diphtheria currently occurs most often in sub-Saharan Africa, India, and Indonesia. In 2015, it resulted in 2,100 deaths, down from 8,000 deaths in 1990. In areas where it is still common, children are most affected. It is rare in the developed world due to widespread vaccination but can re-emerge if vaccination rates decrease. In the United States, 57 cases were reported between 1980 and 2004. Death occurs in 5% to 10% of those diagnosed. The disease was first described in the 5th century BC by Hippocrates. The bacterium was identified in 1882 by Edwin Klebs.
Signs and symptoms
An adherent, dense, grey pseudomembrane covering the tonsils is classically seen in diphtheria.
A diphtheria skin lesion on the leg
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. Within two to three days, diphtheria may destroy healthy tissues in the respiratory system. The dead tissue forms a thick, gray coating that can build up in the throat or nose. This thick gray coating is called a "pseudomembrane". It can cover tissues in the nose, tonsils, voice box, and throat, making it very hard to breathe and swallow. Symptoms can also include cardiac arrhythmias, myocarditis, and cranial and peripheral nerve palsies.
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.
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. Contact with any lesions on the skin can also lead to transmission of diphtheria, but this is uncommon. Indirect infections can occur, as well. If an infected individual touches a surface or object, the bacteria can be left behind and remain viable. 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.
Diphtheria toxin is produced by C. diphtheriae only when infected with a bacteriophage that integrates the toxin-encoding genetic elements into the bacteria.
Fragment A inhibits the synthesis of new proteins in the affected cell by catalyzing ADP-ribosylation of elongation factorEF-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.
Isolation of C. diphtheriae from a Gram stain or throat culture from a clinical specimen,
Histopathologic diagnosis of diphtheria by Albert's stain
In vivo tests (guinea pig inoculation): Subcutaneous and intracutaneous tests
In vitro test: Elek's gel precipitation test, detection of tox gene by PCR, ELISA, ICA
Upper respiratory tract illness with sore throat
Low-grade fever (above 39 °C (102 °F) is rare)
An adherent, dense, grey pseudomembrane covering the posterior aspect of the pharynx: in severe cases, it can extend to cover the entire tracheobronchial tree.
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.
Quinvaxem is a widely administered pentavalent vaccine, which is a combination of five vaccines in one that protect babies from diphtheria, among other common childhood diseases. Diphtheria vaccine is usually combined at least with tetanus vaccine (Td) and often with pertussis (DTP, DTaP, TdaP, Tdap) vaccines, as well.
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 (consisting of antibodies isolated from the serum of horses that have been challenged with diphtheria toxin). Since antitoxin does not neutralize toxin that is already bound to tissues, delaying its administration increases risk of death. 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:
Erythromycin is given (orally or by injection) for 14 days (40 mg/kg per day with a maximum of 2 g/d), or
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% to 50% of those left untreated can die.
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.
The number of cases has changed over the course of the last 2 decades,[disputed – discuss] specifically throughout developing countries. Better standards of living, mass immunization, improved diagnosis, prompt treatment, and more effective health care have led to the decrease in cases worldwide. However, although outbreaks are rare, they still occur worldwide, especially in developed nations such as Germany among unvaccinated children. In Nazi Germany contagious diseases such as diphtheria were among the leading causes of morbidity; they increased "after the mid-1920s, doubled again between 1932 and 1937, and reached extremely high levels during the war only to decline rapidly thereafter".
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. Between 1991 and 1998 as many as 200,000 cases in the Commonwealth of Independent States were reported, with 5,000 deaths.
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 1883, Edwin Klebs identified the bacterium causing diphtheria and named it Klebs-Loeffler bacterium. The club shape of this 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 person 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.
A diphtheria immunisation scheme in London, 1941
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 1890, Shibasaburo Kitasato and Emil von Behring immunized guinea pigs with heat-treated diphtheria toxin. 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 antibodies 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. 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.
In 1905, Franklin Royer, from Philadelphia's Municipal Hospital, published a paper urging timely treatment for diphtheria and adequate doses of antitoxin. In 1906, Clemens Pirquet and Béla 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 significantly in 1924.
A poster from the United Kingdom advertising diphtheria immunisation (published prior to 1962)
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, each year an estimated 100,000 to 200,000 diphtheria cases and 13,000 to 15,000 deaths occurred in the United States. 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 (a modified version of the toxin used for vaccination) by treating it with aluminum salts. Vaccination with toxoid was not widely used until the early 1930s. In 1939, Dr. Nora Wattie Principal Medical Officer (Maternity and Child Welfare) introduced immunisation clinics across Glasgow, and promoted mother and child health education, resulting in virtual eradication of the infection in the city.
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 1975, an outbreak of cutaneous diphtheria in Seattle, Washington was reported .
In 1994, the Russian Federation had 39,703 diphtheria cases. By contrast, in 1990, only 1,211 cases were reported. Between 1990 and 1998, diphtheria caused 5000 deaths in the countries of the former Soviet Union.
^Youwang Y.; Jianming D.; Yong X.; Pong Z. (1992). "Epidemiological features of an outbreak of diphtheria and its control with diphtheria toxoid immunization". International Journal of Epidemiology. 21 (4): 807-11. doi:10.1093/ije/21.4.807. PMID1521987.
^Hogg R. A.; Wessels J.; Hart A.; Efstratiou A.; De Zoysa G.; Mann T.; Pritchard G. C. (2009). "Possible zoonotic transmission of toxigenic Corynebacterium ulcerans from companion animals in a human case of fatal diphtheria". The Veterinary Record. 165 (23): 691-2. doi:10.1136/vr.165.23.691 (inactive 19 January 2021). PMID19966333.CS1 maint: DOI inactive as of January 2021 (link)
^ abcAtkinson W, Hamborsky J, McIntyre L, Wolfe S, eds. (2007). "Diphtheria"(PDF). Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book) (10 ed.). Washington, D.C.: Public Health Foundation. pp. 59-70. Archived(PDF) from the original on 27 September 2007.
^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 inflammations of mucous tissue, and in particular diphtheria or skin inflammation, known by the name of croup, malignant throat infection, gangrenous throat infection, etc.] 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 ?, ... " ( ... Mr. Bretonneau thought it appropriate to call it diphtheria, derived from ? [diphthera], ... )
^"Diphtheria". Online Etymology Dictionary. Archived from the original on 13 January 2013. Retrieved 2012.
^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.
^Lilienfeld, David E. (Spring 2008). "The first pharmacoepidemiologic investigations: national drug safety policy in the United States, 1901-1902". Perspect Biol Med. 51 (2): 188-198. doi:10.1353/pbm.0.0010. PMID18453724. S2CID30767303.
^Royer, Franklin (1905). "The Antitoxin Treatment of Diphtheria, with a Plea for Rational Dosage in Treatment and in Immunizing". Cite journal requires |journal= (help)
^Harnisch, JP; Tronca E; Nolan CM; Turck M; Holmes KK (1 July 1989). "Diphtheria among alcoholic urban adults. A decade of experience in Seattle". Annals of Internal Medicine. 111 (1): 71-82. doi:10.7326/0003-4819-111-1-71. PMID2472081.