Classification and external resources
Diphtheria causes a characteristic swollen neck, sometimes referred to as “bull neck”.
ICD-10 A36
ICD-9 032
DiseasesDB 3122
MedlinePlus 001608
eMedicine emerg/138 med/459 oph/674 ped/596
MeSH D004165

Diphtheria (from facultative anaerobic, Gram-positive bacterium.[1][2] It is characterized by sore throat, low fever, and an adherent membrane (a pseudomembrane) on the tonsils, pharynx, and/or nasal cavity.[3] A milder form of diphtheria can be restricted to the skin. Less common consequences include myocarditis (about 20% of cases)[4] and peripheral neuropathy (about 10% of cases).[5]

Diphtheria is an infectious disease spread by direct physical contact or breathing the aerosolized secretions of infected individuals. Historically quite common, diphtheria has largely been eradicated in developed nations through widespread vaccination. In the United States, for example, there were 53 reported cases of diphtheria between 1980 and 2000,[6] but in the 21st century only two cases of diphtheria have been reported, the last of which was in 2012.[7] The diphtheria–pertussistetanus (DPT) vaccine is recommended for all school-age children in the U.S., and 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 1
    • Diphtheritic croup 1.1
  • Mechanism 2
  • Diagnosis 3
    • Laboratory criteria 3.1
    • Clinical criteria 3.2
    • Case classification 3.3
  • Prevention 4
  • Treatment 5
  • Epidemiology 6
  • History 7
  • References 8
  • Further reading 9
  • External links 10

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 bloodstained nasal discharge and lymphadenopathy.[8][9] 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",[10] "true croup",[11][12] or sometimes simply as "croup".[13] 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.[14]


Diphtheria toxin is produced by C. diphtheriae only when infected with a bacteriophage that integrates the toxin-encoding genetic elements into the bacteria.[15][16]

Diphtheria toxin is a single, 60kDa 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.


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,[9] or
  • Histopathologic diagnosis of diphtheria by a stain called "Albert's Stain".

Clinical criteria

  • Upper respiratory tract illness with sore throat
  • Low-grade fever (>102 °F (39 °C) 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.

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.


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.[17]


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.[6]

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[18] either:

  • Metronidazole
  • Erythromycin (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.

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.


Disability-adjusted life year for diphtheria per 100,000 inhabitants in 2004
  no data
  ≤ 1
  ≥ 50
Diphtheria cases reported to the World Health Organization between 1997 and 2006:
  no data
  1-49 reported cases
  Between 50 and 99 reported cases
  Over 100 reported cases

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%.[6] In 2010 it caused about 2,900 deaths down from 6,300 in 1990.[19]

Outbreaks, though very rare, still occur worldwide, including 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.[20] This was so great an increase that diphtheria was cited in the Guinness Book of World Records as "most resurgent disease".


In 1613, Spain experienced an epidemic of diphtheria. The year is known as "El Año de los Garrotillos" (The Year of Strangulations) in history of Spain.[21]

In 1735, a diphtheria epidemic swept through New England.[22]

Before 1826, diphtheria was known by different names across the world. In England, it was known as Boulogne sour throat, as it spread from France. In 1826, Pierre Bretonneau gave the name to disease as diphtérite (from Greek diphthera "leather") describing the appearance of pseudomembrane in the throat.[23][24]

In 1856, Victor Fourgeaud described an epidemic of diphtheria in California.[25]

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[26] 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 Corynebacterium diphtheriae in 1884.[27] He used Koch's postulates to prove association between Corynebacterium 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 obstructed larynx in 1885. It soon replaced tracheostomy as the emergency diphtheric intubation method.[28]

In 1888, Emile Roux and Alexandre Yersin showed that a substance produced by C. diphtheriae caused symptoms of diphtheria in animals.[29][30]

In 1890, Shibasaburo Kitasato and Emil von Behring immunized guinea pigs with heat-treated diphtheria toxin.[31] The first cure of a person with diphtheria is dated to the 1891 Christmas holiday in Berlin.[32] Von Behring won the first Nobel Prize in medicine in 1901 for his work on diphtheria.

In 1895, Mulford Company of Philadelphia started production and testing of diphtheria antitoxin in the United States.[33] 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 first ever standardization of biological product, and played an important role in future developmental work on sera and vaccines.

In 1901, 10 out 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[34] played an important part in initiating federal regulation of biologic products.[35]

On January 7, 1904, Ruth Cleveland died of diphtheria at the age of twelve years old 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.[36][37]

In 1905, Franklin Royer, from Philadelphia’s Municipal Hospital, published a paper urging timely treatment for diphtheria and adequate doses of antitoxin.[38] 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 preexistent 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.[39]

A poster from the United Kingdom advertising diphtheria immunisation (published prior to 1962)

In 1919, in Dallas, Texas, U.S.A., 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.[40]

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.[6] Children represented a large majority of these cases and fatalities. One of the most famous 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.[41]

In 1943, diphtheria outbreaks accompanied war and disruption in Europe. There were 1 million cases in Europe, with 50,000 deaths.

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

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

In 1975, an outbreak of cutaneous diphtheria in Seattle, Washington was reported .[42]

In 1994, the Russian Federation saw 39,703 diphtheria cases. In contrast, in 1990, there had been only 1,211 cases.[43]

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.[44]

In 2013, 3 children died of diphtheria in Hyderabad, India.[45]


  1. ^ Office of Laboratory Security, Public Health Agency of Canada Corynebacterium diphtheriae Material Safety Data Sheet. January 2000.
  2. ^ Corynebacterium diphtheriae only produces diphtheria toxin when lysogenized by beta phage
  3. ^ Ryan KJ, Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. pp. 299–302.  
  4. ^ Havaldar, PV; Sankpal MN; Doddannavar RP. (2000). "Diphtheritic myocarditis: clinical and laboratory parameters of prognosis and fatal outcome". Annals of Tropical Paediatrics 20 (3): 209–15.  
  5. ^ Solders, G; Nennesmo I; Persson A. (1989). "Diphtheritic neuropathy, an analysis based on muscle and nerve biopsy and repeated neurophysiological and autonomic function tests". J Neurol Neurosurg Psychiatry 52 (7): 876–80.  
  6. ^ a b c d Atkinson W, Hamborsky J, McIntyre L, Wolfe S, eds. (2007). Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book) in: Diphtheria. (10 ed.). Washington DC: Public Health Foundation. pp. 59–70. 
  7. ^ [1].
  8. ^ http://www.nhs.uk/Conditions/Diphtheria/Pages/Symptoms.aspx
  9. ^ a b http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002575/
  10. ^ Loving, Starling (5 October 1895). "Something concerning the diagnosis and treatment of false croup".  
  11. ^ Cormack, John Rose (8 May 1875). "Meaning of the Terms Diphtheria, Croup, and Faux Croup".  
  12. ^ Bennett, James Risdon (8 May 1875). "True and False Croup".  
  13. ^ Beard, George Miller (1875). Our Home Physician: A New and Popular Guide to the Art of Preserving Health and Treating Disease. New York: E. B. Treat. pp. 560–564. Retrieved 15 April 2014. 
  14. ^ Vanderpool, Patricia (December 2012). "Recognizing croup and stridor in children". American Nurse Today 7 (12). Retrieved 15 April 2014. 
  15. ^ Victor J Freeman (1951). "Studies on the Virulence of Bacteriophage-Infected Strains of Corynebacterium Diphtheriae". Journal of Bacteriology 61 (6): 675–688.  
  16. ^ Freeman VJ, Morse IU; Morse (1953). "Further Observations on the Change to Virulence of Bacteriophage-Infected Avirulent Strains of Corynebacterium Diphtheriae". Journal of Bacteriology 63 (3): 407–414.  
  17. ^ "Immunisation and Pentavalent Vaccine".  
  18. ^ The first version of this article was adapted from the 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.
  19. ^ Lozano, R; Naghavi, M; Foreman, K; Lim, S; Shibuya, K; Aboyans, V; Abraham, J; Adair, T; Aggarwal, R; Ahn, SY; Alvarado, M; Anderson, HR; Anderson, LM; Andrews, KG; Atkinson, C; Baddour, LM; Barker-Collo, S; Bartels, DH; Bell, ML; Benjamin, EJ; Bennett, D; Bhalla, K; Bikbov, B; Bin Abdulhak, A; Birbeck, G; Blyth, F; Bolliger, I; Boufous, S; Bucello, C et al. (Dec 15, 2012). "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010". Lancet 380 (9859): 2095–128.  
  20. ^ "Diphtheria in the Former Soviet Union: Reemergence of a Pandemic Disease". CDC, Emerging Infectious Diseases. 1998-10-01. 
  21. ^ LAVAL, Enrique (March 2006). "El garotillo (Difteria) en España (Siglos XVI y XVII)". Revista chilena de infectología 23.  
  22. ^ Boston Gazette. March 18, 1735. 
  23. ^ Pierre Bretonneau, 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, 1826).
    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], … )
  24. ^ "Diphtheria". Online Etymology Dictionary. Retrieved 29 November 2012. 
  25. ^ Fourgeaud, Victor J. (1858). Diphtheritis: a concise historical and critical essay on the late epidemic pseudo-membranous sore throat of California (1856-7), with a few remarks illustrating the diagnosis, pathology, and treatment of the disease. California: Sacramento: J. Anthony & Co., 1858. 
  26. ^ Klebs (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.
  27. ^ Loeffler (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.
  28. ^ Gifford, Robert R. (March 1970). "The O'Dwyer tube; development and use in laryngeal diphtheria". Clin Pediatr (Phila) 9 (3): 179–185.  
  29. ^ E. Roux and A. Yersin (December 1888) "Contribution à l'étude de la diphthérte" (Contribution to the study of diphtheria), Annales de l'Institute Pasteur, 2 : 629-661.
  30. ^ Parish, Henry (1965). A history of immunization. E. & S. Livingstone. p. 120. 
  31. ^ 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.
  32. ^ John M. Barry, The Great Influenza; The Story of the Deadliest Pandemic in History (New York: Penguin Books, c2004, 2005) p. 70.
  33. ^ Diphtheria Antitoxin. The Company. 1903. 
  34. ^ "The Tetanus Cases in Camden, N.J". JAMA. XXXVII (23): 1539–1540. December 7, 1901.  
  35. ^ 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.  
  36. ^ Ruth Cleveland (1891-1904) Find A Grave
  37. ^ Ruth Cleveland WorldHeritage
  38. ^ Royer, Franklin (1905). "The Antitoxin Treatment of Diphtheria, with a Plea for Rational Dosage in Treatment and in Immunizing". 
  39. ^ "United States mortality rate from measles, scarlet fever, typhoid, whooping cough, and diphtheria from 1900–1965". HealthSentinel.com. Archived from the original on 2008-05-14. Retrieved 2008-06-30. 
  40. ^ Wilson, Graham (2002). The Hazards of Immunization. Continuum International Publishing Group, Limited, 2002. p. 20.  
  41. ^ "History of Vaccines". Retrieved 28 October 2013. 
  42. ^ Harnisch, JP; Tronca E; Nolan CM; Turck M; Holmes KK (July 1, 1989). "Diphtheria among alcoholic urban adults. A decade of experience in Seattle". Annals of Internal Medicine 111 (1): 71–82.  
  43. ^ http://jid.oxfordjournals.org/content/181/Supplement_1/S228.full
  44. ^ "CNN's Anderson Cooper talks with Sean Penn and Dr. Sanjay Gupta about the threat of diphtheria in Haiti.". CNN.com. Retrieved 2010-05-09. 
  45. ^ "Three kids die of diphtheria". The Hindu. Retrieved 2013-08-28. 

Further reading

  • Holmes, R .K. (2005). "Diphtheria and other corynebacterial infections". In Kasper; et al. Harrison's Principles of Internal Medicine (16th ed.). New York: McGraw-Hill.  
  • "Antitoxin dars 1735 and 1740." The William and Mary Quarterly, 3rd Ser., Vol 6, No 2. p. 338.
  • Shulman, S. T. (2004). "The History of Pediatric Infectious Diseases". Pediatric Research 55 (1): 163–176.  

External links

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