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Diphtheria

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"Diphthera" redirects here. For the genus of moth, see Diphthera (moth).
Diphtheria
SpecialtyInfectious disease

Diphtheria is an infection caused by the bacterium Corynebacterium diphtheriae.[1] Signs and symptoms may vary from mild to severe.[2] They usually start two to five days after exposure.[1] Symptoms often come on fairly gradually beginning with a sore throat and fever.[2] In severe cases a grey or white patch develops in the throat.[1][2] This can block the airway and create a barking cough as in croup.[2] The neck may swell in part due to large lymph nodes.[1] A form of diphtheria that involves the skin, eyes, or genitals also exists.[1][2] Complications may include myocarditis, inflammation of nerves, kidney problems, and bleeding problems due to low blood platelets. Myocarditis may result in an abnormal heart rate and inflammation of the nerves may result in paralysis.[1]

Diphtheria is usually spread between people by direct contact or through the air.[1][3] It may also be spread by contaminated objects. Some people carry the bacteria without having symptoms, but can still spread the disease to others. There are three main types of C. diphtheriae causing different severities of disease.[1] The symptoms are due to a toxin produced by the bacteria. Diagnosis can often be made based on the appearance of the throat with confirmation by culture. Previous infection may not prevent against future infection.[2]

A vaccine, known as diphtheria toxoid, is effective for prevention and available in a number of formulations. Three or four doses, given along with tetanus toxoid and acellular pertussis vaccine, are recommended during childhood. Further doses are recommended every ten years. Protection can be verified by measuring the antitoxin level in the blood. Treatment is with the antibiotic erythromycin or penicillin G. These antibiotics may also be used for prevention in those who have been exposed to the infection.[1] A surgical procedure known as a tracheostomy is sometimes needed to open the airway in severe cases.[2]

In 2013, 4,700 cases were officially reported, down from nearly 100,000 in 1980.[4] It is believed, however, that about a million cases occurred per year before the 1980s.[2] It currently occurs most often in Sub-Saharan Africa, India, and Indonesia.[2][5] In 2013, it resulted in 3,300 deaths down from 8,000 deaths in 1990.[6] In areas where it is still common, children are most affected. It is rare in the developed world due to widespread vaccination.[2] In the United States 57 cases were reported between 1980 and 2004. Death occurs in between 5% and 10% of those affected. The disease was first described in the 5th century BC by Hippocrates. The bacterium was discovered in 1882 by Edwin Klebs.[1]

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.[7][8] 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",[9] "true croup",[10][11] or sometimes simply as "croup".[12] 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.[13]

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 [14] It is also possible that contact with any lesions on the skin can also lead to transmission, but it is uncommon.[15] 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. There is also evidence that diphtheria has the potential to be zoonotic, but this has yet tot be confirmed. The strain, Corynebacterium ulcerans, has been found in some animals which would suggest zoonotic potential [16]

Mechanism

Diphtheria toxin is produced by C. diphtheriae only when infected with a bacteriophage that integrates the toxin-encoding genetic elements into the bacteria.[17][18]

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, catalysing 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.[citation needed]

Diagnosis

The current clinical case definition of diphtheria used by the United States' 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,[8] or
  • Histopathologic diagnosis of diphtheria by a stain called "Albert's Stain".

Clinical criteria

  • 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.

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.

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.[19] 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 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.[20]

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[21] 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.

Epidemiology

Disability-adjusted life year for diphtheria per 100,000 inhabitants in 2004
  no data
  ≤ 1
  1–2
  2–3
  3–4
  4–5
  5–6
  6–7
  7–9
  9–10
  10–15
  15–50
  ≥ 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%.[20] In 2013 it resulted in 3,300 deaths down from 8,000 deaths in 1990.[6]

Outbreaks, though very rare, still occur worldwide, including in developed nations, such as Germany among non-vaccinated children, and Canadaneeds citation. After the breakup of the former Soviet Union in the early 1990s, 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.[22]

History

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.[23]

In 1735, a diphtheria epidemic swept through New England.[24]

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.[25][26]

In 1856, Victor Fourgeaud described an epidemic of diphtheria in California.[27]

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[28] 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.[29] 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.[30]

In 1888, Emile Roux and Alexandre Yersin showed that a substance produced by C. diphtheriae caused symptoms of diphtheria in animals.[31][32]

In 1890, Shibasaburo Kitasato and Emil von Behring immunized guinea pigs with heat-treated diphtheria toxin.[33] The first cure of a person with diphtheria is dated to the 1891 Christmas holiday in Berlin.[34] 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.[35] 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 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[36] played an important part in initiating federal regulation of biologic products.[37]

On 7 January 1904, Ruth Cleveland died of diphtheria at the age of twelve 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.[38]

In 1905, Franklin Royer, from Philadelphia's Municipal Hospital, published a paper urging timely treatment for diphtheria and adequate doses of antitoxin.[39] 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.[40]

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.[41]

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.[20] 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.[42]

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 .[43]

In 1994, the Russian Federation saw 39,703 diphtheria cases. In contrast, in 1990, there had been only 1,211 cases.[44]

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.[45]

In 2013, 3 children died of diphtheria in Hyderabad, India.[46]

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.[47] It was the first case of diphtheria in the country since 1986 as reported by "El Mundo"[48] or from 1998, as reported by WHO.[49]

In March 2016, a 3-year-old girl died of diphtheria in the University Hospital of Antwerp, Belgium.[50]

In June 2016, 3 cases of a 3-year-old, 5 year old & 7-year-old girl died of diphtheria in Kedah & Malacca, Sabah Malaysia.[51]

References

Template:Research help

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  2. ^ a b c d e f g h i j "Diphtheria vaccine" (PDF). Wkly Epidemiol Rec. 81 (3): 24–32. 20 January 2006. PMID 16671240.
  3. ^ Kowalski, Wladyslaw (2012). Hospital airborne infection control. Boca Raton, Florida: CRC Press. p. 54. ISBN 9781439821961.
  4. ^ "Diphtheria". who.int. 3 September 2014. Retrieved 27 March 2015.
  5. ^ Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (8 ed.). Elsevier Health Sciences. 2014. p. 2372. ISBN 9780323263733.
  6. ^ a b GBD 2013 Mortality and Causes of Death, Collaborators (17 December 2014). "Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013". Lancet. 385: 117–71. doi:10.1016/S0140-6736(14)61682-2. PMC 4340604. PMID 25530442. {{cite journal}}: |first1= has generic name (help)CS1 maint: numeric names: authors list (link)
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  8. ^ a b "Updating PubMed Health". PubMed Health. Retrieved 28 June 2015.
  9. ^ Loving, Starling (5 October 1895). "Something concerning the diagnosis and treatment of false croup". JAMA: the Journal of the American Medical Association. XXV (14): 567–573. doi:10.1001/jama.1895.02430400011001d. Retrieved 16 April 2014.
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  12. ^ 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.
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  15. ^ 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. PMID 1521987.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ 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. PMID 19966333.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ Freeman, Victor J (1951). "Studies on the Virulence of Bacteriophage-Infected Strains of Corynebacterium Diphtheriae". Journal of Bacteriology. 61 (6): 675–688. PMC 386063. PMID 14850426.
  18. ^ 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. PMC 169283. PMID 14927573.
  19. ^ "Immunisation and Pentavalent Vaccine". UNICEF.
  20. ^ a b c Atkinson W, Hamborsky J, McIntyre L, Wolfe S, eds. (2007). "Diphtheria". Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book) (PDF) (10 ed.). Washington, D.C.: Public Health Foundation. pp. 59–70.
  21. ^ The first version of this article was adapted from the CDC 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.
  22. ^ "Diphtheria in the Former Soviet Union: Reemergence of a Pandemic Disease". CDC, Emerging Infectious Diseases. 1 October 1998.
  23. ^ Laval, Enrique (March 2006). "El garotillo (Difteria) en España (Siglos XVI y XVII)". Revista chilena de infectología. 23. doi:10.4067/S0716-10182006000100012.
  24. ^ "ON THE TREATMENT OF DIPHTHERIA IN 1735". Pediatrics. 55 (1). American Academy of Pediatrics: 43. 1975.
  25. ^ 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 ΔΙΦθΕΡΑ, … " ( … Mr. Bretonneau thought it appropriate to call it diphtheria, derived from ΔΙΦθΕΡΑ [diphthera], … )
  26. ^ "Diphtheria". Online Etymology Dictionary. Retrieved 29 November 2012.
  27. ^ 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.
  28. ^ 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.
  29. ^ 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.
  30. ^ Gifford, Robert R. (March 1970). "The O'Dwyer tube; development and use in laryngeal diphtheria". Clin Pediatr (Phila). 9 (3): 179–185. doi:10.1177/000992287000900313. PMID 4905866.
  31. ^ 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.
  32. ^ Parish, Henry (1965). A history of immunization. E. & S. Livingstone. p. 120.
  33. ^ 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.
  34. ^ Barry, John M. (2004) The Great Influenza; The Story of the Deadliest Pandemic in History. New York: Penguin Books. p. 70. ISBN 0143036491.
  35. ^ H. K. Mulford Company (1903). Diphtheria Antitoxin. The Company.
  36. ^ "The Tetanus Cases in Camden, N.J". JAMA. XXXVII (23): 1539–1540. 7 December 1901. doi:10.1001/jama.1901.02470490037010. Retrieved 29 November 2012.
  37. ^ 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. PMID 18453724.
  38. ^ "Ruth Cleveland (1891 - 1904) - Find A Grave Memorial". Retrieved 28 June 2015.
  39. ^ Royer, Franklin (1905). "The Antitoxin Treatment of Diphtheria, with a Plea for Rational Dosage in Treatment and in Immunizing". {{cite journal}}: Cite journal requires |journal= (help)
  40. ^ "United States mortality rate from measles, scarlet fever, typhoid, whooping cough, and diphtheria from 1900–1965". HealthSentinel.com. Archived from the original on 14 May 2008. Retrieved 30 June 2008.
  41. ^ Wilson, Graham (2002). The Hazards of Immunization. Continuum International Publishing Group, Limited, 2002. p. 20. ISBN 9780485263190.
  42. ^ "Disease and Vaccines". historyofvaccines.orgHistory of Vaccines. Retrieved 28 October 2013.
  43. ^ 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. PMID 2472081.
  44. ^ Tatochenko, Vladimir; Mitjushin, I. L. (2000). "Contraindications to Vaccination in the Russian Federation". The Journal of Infectious Diseases. 181: S228–31. doi:10.1086/315567. PMID 10657219.
  45. ^ "CNN's Anderson Cooper talks with Sean Penn and Dr. Sanjay Gupta about the threat of diphtheria in Haiti". CNN. 10 May 2010.
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  47. ^ "Parents of diphtheria-stricken boy feel "tricked" by anti-vaccination groups". El Pais. 5 June 2015.
  48. ^ "Primer caso de difteria en España en casi 30 años". El Mundo. 2 June 2015.
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  50. ^ "Meisje (3) overlijdt aan difterie in ziekenhuis". De Standaard. 17 March 2016.
  51. ^ Murali, R.S.N. (21 June 2016). "Malacca Health Dept works to contain diptheria after seven-year-old dies". thestar.com.my.

Further reading

  • Holmes, R .K. (2005). "Diphtheria and other corynebacterial infections". In Kasper; et al. (eds.). Harrison's Principles of Internal Medicine (16th ed.). New York: McGraw-Hill. ISBN 0-07-139140-1.
  • "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. doi:10.1203/01.PDR.0000101756.93542.09. PMID 14605240.
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