diphtheria

File:Diphtheria bull neck.5325 lores.jpg

File:A diphtheria skin lesion on the leg. PHIL 1941 lores.jpg

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; hoarseness; cough; headache; difficulty swallowing; painful swallowing; difficulty breathing; rapid breathing; foul-smelling and bloodstained nasal discharge; and lymphadenopathy.{{cite web|url=http://www.nhs.uk/Conditions/Diphtheria/Pages/Symptoms.aspx|title=Diphtheria—Symptoms—NHS Choices|access-date=28 June 2015|url-status=live|archive-url=https://web.archive.org/web/20150628170154/http://www.nhs.uk/Conditions/Diphtheria/Pages/Symptoms.aspx|archive-date=28 June 2015}}{{MedlinePlusEncyclopedia|001608|Diphtheria}} 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.{{cite web|title=Diphtheria Symptoms|url=https://www.cdc.gov/diphtheria/symptoms/|website=www.cdc.gov|access-date=11 January 2025|language=en-us|date=12 February 2024}} Symptoms can also include cardiac arrhythmias, myocarditis, and cranial and peripheral nerve palsies.{{cite web |url=https://www.lecturio.com/concepts/diphtheria/| title=Diphtheria|website=The Lecturio Medical Concept Library | date=4 August 2020|access-date= 12 July 2021}}

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,"{{cite journal|last=Loving|first=Starling|title=Something concerning the diagnosis and treatment of false croup|journal=JAMA: The Journal of the American Medical Association|date=5 October 1895|volume=XXV|issue=14|pages=567–573|url=https://books.google.com/books?id=-FQcAQAAMAAJ&pg=PA567|access-date=16 April 2014|doi=10.1001/jama.1895.02430400011001d|url-status=live|archive-url=https://web.archive.org/web/20140704192208/http://books.google.com/books?id=-FQcAQAAMAAJ&pg=PA567|archive-date=4 July 2014}} "true croup,"{{cite journal|last=Cormack|first=John Rose|title=Meaning of the Terms Diphtheria, Croup, and Faux Croup|journal=British Medical Journal|date=8 May 1875|volume=1|issue=749|page=606|doi=10.1136/bmj.1.749.606|pmc=2297755|pmid=20747853 }}{{cite journal|last=Bennett|first=James Risdon|title=True and False Croup|journal=British Medical Journal|date=8 May 1875 |volume=1 |issue=749 |pages=606–607 |doi=10.1136/bmj.1.749.606-a|pmc=2297754|pmid=20747854 }} or sometimes simply as "croup."{{cite book|last=Beard|first=George Miller|title=Our Home Physician: A New and Popular Guide to the Art of Preserving Health and Treating Disease|year=1875|publisher=E. B. Treat|location=New York|pages=[https://archive.org/details/ourhomephysicia00beargoog/page/n567 560]–564|url=https://archive.org/details/ourhomephysicia00beargoog|access-date=15 April 2014}} 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.{{cite journal|last=Vanderpool |first=Patricia |title=Recognizing croup and stridor in children |journal=American Nurse Today |date=December 2012 |volume=7 |number=12 |url=http://www.americannursetoday.com/article.aspx?id=9752&fid=9722 |access-date=15 April 2014 |url-status=dead |archive-url=https://web.archive.org/web/20140416174601/http://www.americannursetoday.com/article.aspx?id=9752&fid=9722 |archive-date=16 April 2014 }}

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.[https://www.cdc.gov/diphtheria/about/causes-transmission.html Diphtheria Causes and Transmission] {{webarchive|url=https://web.archive.org/web/20140413123404/http://www.cdc.gov/diphtheria/about/causes-transmission.html |date=13 April 2014 }}. 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 is uncommon.{{cite journal|author1=Youwang Y. |author2=Jianming D. |author3=Yong X. |author4=Pong Z. |title=Epidemiological features of an outbreak of diphtheria and its control with diphtheria toxoid immunization|journal=International Journal of Epidemiology|volume=21|issue=4|pages=807–11|pmid=1521987|year=1992 |doi=10.1093/ije/21.4.807}} 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.{{cite journal|author1=Hogg R. A. |author2=Wessels J. |author3=Hart A. |author4=Efstratiou A. |author5=De Zoysa G. |author6=Mann T. |author7=Pritchard G. C. |title=Possible zoonotic transmission of toxigenic Corynebacterium ulcerans from companion animals in a human case of fatal diphtheria|journal=The Veterinary Record|volume=165|issue=23|pages=691–2|pmid=19966333|year=2009 |doi=10.1136/vr.165.23.691|s2cid=8726176 }}

Diphtheria toxin (DT) is produced only by C. diphtheriae infected with a certain type of bacteriophage.{{cite journal | author = Freeman, Victor J | title = Studies on the Virulence of Bacteriophage-Infected Strains of Corynebacterium Diphtheriae | journal = Journal of Bacteriology | year = 1951 | pages = 675–688 | pmid = 14850426 | volume = 61 | issue = 6 | pmc=386063| doi = 10.1128/JB.61.6.675-688.1951 }}{{cite journal | author = Freeman VJ, Morse IU | title = Further Observations on the Change to Virulence of Bacteriophage-Infected Avirulent Strains of Corynebacterium Diphtheriae | journal = Journal of Bacteriology | year = 1953 | pages = 407–414 | pmid = 14927573 | volume = 63 | issue = 3 | pmc=169283| last2 = Morse | doi = 10.1128/JB.63.3.407-414.1952 }} Toxinogenicity is determined by phage conversion (also called lysogenic conversion); i.e., the ability of the bacterium to make DT changes as a consequence of infection by a particular phage. DT is encoded by the tox gene. Strains of corynephage are either tox⁺ (e.g., corynephage β) or tox⁻ (e.g., corynephage γ). The tox gene becomes integrated into the bacterial genome.{{cite journal |last1=Holmes |first1=R. K. |title=Biology and molecular epidemiology of diphtheria toxin and the tox gene. |journal=The Journal of Infectious Diseases |date=2000 |volume=181 |issue=Supplement 1 |pages=S156–S167 |doi=10.1086/315554 |pmid=10657208|doi-access=free }} The chromosome of C. diphtheriae has two different but functionally equivalent bacterial attachment sites (attB) for integration of β prophage into the chromosome.

The diphtheria toxin precursor is a protein of molecular weight 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. DT-B is a recognition subunit that gains entry of DT 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, DT is split by a trypsin-like protease into DT-A and DT-B. The acidity of the endosome causes DT-B to create pores in the endosome membrane, thereby catalysing the release of DT-A into the 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.{{cite web | title = Entrez Gene: EEF2 eukaryotic translation elongation factor 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1938}}

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.{{cite journal | author = Collier JR | title = Diphtheria toxin: mode of action and structure. | journal = Bacteriological Reviews | year = 1975 | pages = 54–85 | pmid = 164179 | volume = 39 | issue = 1 | pmc=413884| doi = 10.1128/MMBR.39.1.54-85.1975 }}

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.

• 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.{{citation needed|date=March 2023}}
• 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 {{convert|39|C|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.

{{Main|Diphtheria vaccine}}

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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.{{cite web |url=http://www.unicef.org/republicadominicana/english/survival_development_12792.htm |title=Immunisation and Pentavalent Vaccine |work=UNICEF |url-status=live |archive-url=https://web.archive.org/web/20140729161800/http://www.unicef.org/republicadominicana/english/survival_development_12792.htm |archive-date=29 July 2014 }}

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). 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.{{Cite book | vauthors = Atkinson W, Hamborsky J, McIntyre L, ((Wolfe S, eds.)) | chapter = Diphtheria | title = Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book) | edition = 10 | pages = 59–70 | location = Washington, D.C. | publisher = Public Health Foundation | year = 2007 | chapter-url = https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/dip.pdf | url-status = live | archive-url = https://web.archive.org/web/20070927000637/http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/dip.pdf | archive-date = 27 September 2007 | df = dmy-all }}

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) recommendsThe first version of this article was adapted from the Centers for Disease Control and Prevention document [https://wwwn.cdc.gov/nndss/conditions/diphtheria/case-definition/1995/ "Diphtheria (Corynebacterium diphtheriae) 1995 Case Definition"] {{webarchive|url=https://web.archive.org/web/20161220041755/https://wwwn.cdc.gov/nndss/conditions/diphtheria/case-definition/1995/ |date=20 December 2016 }}. 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:

• Metronidazole
• 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 40–50% of those left untreated can die.{{citation needed|date=June 2021}}{{Cite web |date=September 9, 2022 |title=Diagnosis, Treatment, and Complications |url=https://www.cdc.gov/diphtheria/about/diagnosis-treatment.html |access-date=March 7, 2023 |website=Centers for Disease Control and Prevention}}

File:Diphtheria world map - DALY - WHO2004.svg for diphtheria per 100,000 inhabitants in 2004:{{Div col|small=yes|colwidth=10em}}

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File:Diphtheria_Cases_-_1997_-_2006.svg between 1997 and 2006:

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{{legend|#E0E080|1–49 reported cases}}

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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%. In 2013, it resulted in 3,300 deaths, down from 8,000 deaths in 1990. Better standards of living, mass immunization, improved diagnosis, prompt treatment, and more effective health care have led to a decrease in cases worldwide.

In 1613, Spain experienced an epidemic of diphtheria, referred to as {{lang|es|El Año de los Garrotillos}} (The Year of Strangulations).{{cite journal|last=Laval|first=Enrique|title=El garotillo (Difteria) en España (Siglos XVI y XVII)|journal=Revista Chilena de Infectología|date=March 2006|volume=23|issue=1|pages=78–80|doi=10.4067/S0716-10182006000100012|pmid=16462970|doi-access=free}}

In 1705, the Mariana Islands experienced an epidemic of diphtheria and typhus simultaneously, reducing the population to about 5,000 people.{{cite book |last1=Rogers |first1=Robert F. |title=Destiny's Landfall: A History of Guam |date=June 30, 2011 |publisher=University of Hawai'i Press |location=Honolulu, Hawai'i |isbn=978-0-8248-3334-3 |page=72}}

In 1735, a diphtheria epidemic swept through New England.{{cite journal|journal=Pediatrics|year=1975|volume=55|pages=43|issue=1|title=On the Treatment of Diphtheria in 1735|url=http://pediatrics.aappublications.org/content/55/1/43|url-access=subscription|publisher= American Academy of Pediatrics|doi=10.1542/peds.55.1.43|s2cid=245183270}}

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 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) [http://babel.hathitrust.org/cgi/pt?id=mdp.39015062233708;view=1up;seq=217 "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], … ){{cite web|title=Diphtheria|url=http://www.etymonline.com/index.php?term=diphtheria|work=Online Etymology Dictionary|access-date=29 November 2012|url-status=live|archive-url=https://web.archive.org/web/20130113162016/http://www.etymonline.com/index.php?term=diphtheria|archive-date=13 January 2013}}

In 1856, Victor Fourgeaud described an epidemic of diphtheria in California.{{cite book |last1=Fourgeaud |first1=Victor John |title=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 |date=1858 |publisher=J. Anthony |oclc=11760038 |url=http://resource.nlm.nih.gov/101179231 }}{{pn|date=February 2024}}

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.{{cite web|title=Diaries and Letters – Princess Alice of Hesse and by Rhine|url=http://www.alexanderpalace.org/palace/alicehessebio.html}}{{Self-published inline|date=November 2021|certain=y}}

In 1883, Edwin Klebs identified the bacterium causing diphtheria,Klebs, E. (1883) [https://books.google.com/books?id=bs0vAAAAIAAJ&pg=RA1-PA139 "III. Sitzung: Ueber Diphtherie" (Third session: On diphtheria), Verhandlungen des Congresses für innere Medicin. Zweiter Congress gehalten zu Wiesbaden, 18.-23. April 1883] {{webarchive|url=https://web.archive.org/web/20160522005528/https://books.google.com/books?id=bs0vAAAAIAAJ&pg=RA1-PA139 |date=22 May 2016 }} (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.{{Cite web |title=Corynebacterium diphtheriae |url=https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=info&id=1717 |website=NCBI Taxonomy browser }}

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.{{citation needed|date=November 2017}}File:Diphtheria Immunisation Scheme, London, England, 1941 D3184.jpg

In 1885, Joseph P. O'Dwyer introduced the O'Dwyer tube for laryngeal intubation in patients with an obstructed larynx. It soon replaced tracheostomy as the emergency diphtheric intubation method.{{cite journal|last=Gifford|first=Robert R.|s2cid=37108037|title=The O'Dwyer tube; development and use in laryngeal diphtheria|journal=Clin Pediatr (Phila)|date=March 1970|volume=9|issue=3|pages=179–185|doi=10.1177/000992287000900313|pmid=4905866}}

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) [https://archive.org/stream/annalesdelinstit02inst#page/n686/mode/1up "Contribution à l'étude de la diphthérte"] {{webarchive|url=https://web.archive.org/web/20160315082939/https://archive.org/stream/annalesdelinstit02inst |date=15 March 2016 }} (Contribution to the study of diphtheria), Annales de l'Institute Pasteur, 2 : 629–661.{{cite book|last=Parish|first=Henry|title=A history of immunization|year=1965|publisher=E. & S. Livingstone|page=120}}

In 1890, Shibasaburō Kitasato and Emil von Behring immunized guinea pigs with heat-treated diphtheria toxin.Behring, E. and Kitasato, S. (1890) [https://archiv.ub.uni-marburg.de/eb/2013/0164/ "Ueber das Zustandekommen der Diphtherie-Immunitat und der Tetanus-Immunitat bei Thieren"] {{webarchive|url=https://web.archive.org/web/20161220042358/https://archiv.ub.uni-marburg.de/eb/2013/0164/ |date=20 December 2016 }} (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 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.{{Cite journal|last=Kaufmann|first=Stefan H. E.|date=8 March 2017|title=Remembering Emil von Behring: from Tetanus Treatment to Antibody Cooperation with Phagocytes|journal=mBio|language=en|volume=8|issue=1|pages=e00117–17|pmid=28246359|pmc=5347343|doi=10.1128/mBio.00117-17}}{{Cite news|url=https://journals.lww.com/academicmedicine/Fulltext/2000/04000/Horses_and_the_Diphtheria_Antitoxin.22.aspx|title=Horses and the Diphtheria Antitoxin|date=April 2000|work=Academic Medicine|language=en-US}} In 1901, Von Behring won the first Nobel Prize in medicine for his work on diphtheria.Emil von Behring [https://www.nobelprize.org/nobel_prizes/medicine/laureates/1901/behring-lecture.html 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.{{cite book|author=H. K. Mulford Company|title=Diphtheria Antitoxin|year=1903|publisher=The Company|url=https://books.google.com/books?id=hV_StgAACAAJ}} Park and Biggs described the method for producing serum from horses for use in diphtheria treatment.{{citation needed|date=November 2017}}

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.{{Cite web |title=Difference Between Serums & Vaccines {{!}} What is - YTread |url=https://youtuberead.com/difference-between-serums-vaccines |access-date=2023-04-02 |website=youtuberead.com |language=en}}

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,{{cite journal|title=The Tetanus Cases in Camden, N.J|journal=JAMA|date=7 December 1901|volume=XXXVII|issue=23|pages=1539–1540|doi=10.1001/jama.1901.02470490037010}} played an important part in initiating federal regulation of biologic products.{{cite journal|last=Lilienfeld|first=David E.|s2cid=30767303|title=The first pharmacoepidemiologic investigations: national drug safety policy in the United States, 1901–1902|journal=Perspect Biol Med|date=Spring 2008|volume=51|issue=2|pages=188–198|doi=10.1353/pbm.0.0010|pmid=18453724}}

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.{{citation needed|date=June 2022}}

In 1905, Franklin Royer, from Philadelphia's Municipal Hospital, published a paper urging timely treatment for diphtheria and adequate doses of antitoxin.{{cite journal|last=Royer|first=Franklin|title=The Antitoxin Treatment of Diphtheria, with a Plea for Rational Dosage in Treatment and in Immunizing|journal = The Therapeutic Gazette|year=1905}} In 1906, Clemens Pirquet and Béla Schick described serum sickness in children receiving large quantities of horse-derived antitoxin.{{cite journal |author=Jackson R |s2cid=7001068 |title=Serum sickness |journal=J Cutan Med Surg |volume=4 |issue=4 |pages=223–5 |date=October 2000 |pmid=11231202 |doi= 10.1177/120347540000400411}}

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.{{Cite web| url=http://www.healthsentinel.com/graphs.php?id=14&event=graphs_print_list_item | title=United States mortality rate from measles, scarlet fever, typhoid, whooping cough, and diphtheria from 1900–1965 |access-date=30 June 2008 |publisher=HealthSentinel.com |archive-url = https://web.archive.org/web/20080514014018/http://www.healthsentinel.com/graphs.php |archive-date = 14 May 2008}}

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. The manufacturer of the antitoxin, the Mulford Company of Philadelphia, paid damages in every case.{{cite book|last=Wilson|first=Graham|title=The Hazards of Immunization|year=2002|publisher=Continuum International Publishing Group, Limited, 2002|isbn=9780485263190|pages=20}}

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. Children represented a large majority of these cases and fatalities. One of the most infamous outbreaks of diphtheria occurred in 1925, in Nome, Alaska; the "Great Race of Mercy" to deliver diphtheria antitoxin is now celebrated by the Iditarod Trail Sled Dog Race.{{Cite web|url=https://www.cdc.gov/about/24-7/savinglives/diphtheria/index.html|title=Iditarod: Celebrating the "Great Race of Mercy" to Stop Diphtheria Outbreak in Alaska {{!}} About {{!}} CDC|date=11 July 2018|website=www.cdc.gov|language=en-us|access-date=5 March 2019}}

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.{{cite web|url=http://www.historyofvaccines.org/content/timelines/diseases-and-vaccines |title=Timeline |at=1926 — Glenny Develops Adjuvant |work=History of Vaccines |access-date=28 October 2013 |url-status=live |archive-url=https://web.archive.org/web/20140701081956/http://www.historyofvaccines.org/content/timelines/diseases-and-vaccines |archive-date=1 July 2014}} Vaccination with toxoid was not widely used until the early 1930s.[https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/dip.pdf 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,{{Cite web |date=March 2021 |title=Nora Isabel Wattie |url=https://mathshistory.st-andrews.ac.uk/Extras/Wattie_Nora/ |url-status=live |archive-url=https://archive.today/20230903042427/https://mathshistory.st-andrews.ac.uk/Extras/Wattie_Nora/ |archive-date=3 September 2023 |access-date=2 September 2023 |website=MacTutor |publication-place=University of St Andrews}} introduced immunisation clinics across Glasgow, and promoted mother and child health education, resulting in virtual eradication of the infection in the city.{{Cite journal|last1=Mackie|first1=Elizabeth M|last2=Scott Wilson|first2=T.|date=12 November 1994|title=Obituary N.I.Wattie|journal=British Medical Journal|volume=309|pages=1297}}

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.{{Cite journal|last1=Baten|first1=Joerg|last2=Wagner|date=2003|title=Autarky, Market Disintegration, and Health: The Mortality and Nutritional Crisis in Nazi Germany 1933–37|journal=Economics and Human Biology |volume=1-1 |issue=1 |pages=1–28 |doi=10.1016/S1570-677X(02)00002-3 |pmid=15463961 |s2cid=36431705 |url=https://www.cesifo.org/DocDL/cesifo_wp800.pdf}}

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.{{cite book |last=Felton|first=Mark|author-link=Mark Felton|date=2009|title=The Real Tenko: Extraordinary True Stories of Women Prisoners of the Japanese|url= |location=Great Britain|publisher=Pen & Sword Military|page=41 |isbn=9781848845503}}

In 1943, diphtheria outbreaks accompanied war and disruption in Europe. The 1 million cases in Europe resulted in 50,000 deaths.{{citation needed|date=March 2017}}

During 1948 in Kyoto, 68 of 606 children died after diphtheria immunization due to improper manufacture of aluminum phosphate toxoid.{{cite book |editor1-first=Kathleen R. |editor1-last=Stratton |editor2-first=Cynthia J. |editor2-last=Howe |editor3-first=Richard B. |editor3-last=Johnston |chapter=Diphtheria and Tetanus Toxoids |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK236292/ |title=Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality |date=1994 |publisher=National Academies Press |isbn=978-0-309-04895-8 }}

In 1974, the World Health Organization included DPT vaccine in their Expanded Programme on Immunization for developing countries.{{cite web | title = Immunization, Vaccines and Biologicals | publisher = World Health Organization | url = https://www.who.int/immunization/programmes_systems/en/ | archive-url = https://web.archive.org/web/20131208072315/http://www.who.int/immunization/programmes_systems/en/ | url-status = dead | archive-date = 8 December 2013 | access-date = 10 May 2020}}{{cite journal |last1=Keja |first1=Ko |last2=Chan |first2=Carole |last3=Hayden |first3=Gregory |last4=Henderson |first4=Ralph H. |title=Expanded Programme on Immunization |journal=World Health Statistics Quarterly |date=1988 |volume=41 |issue=2 |pages=59–63 |pmid=3176515 |hdl=10665/49253 }}

In 1975, an outbreak of cutaneous diphtheria in Seattle, Washington, was reported.{{cite journal|last=Harnisch|first=JP|author2=Tronca E |author3=Nolan CM |author4=Turck M |author5=Holmes KK |title=Diphtheria among alcoholic urban adults. A decade of experience in Seattle|journal=Annals of Internal Medicine|date=1 July 1989|volume=111|issue=1|pages=71–82|pmid=2472081|doi=10.7326/0003-4819-111-1-71}}

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 1994, the Russian Federation had 39,703 diphtheria cases. By contrast, in 1990, only 1,211 cases were reported.{{cite journal|doi=10.1086/315567|pmid=10657219|title=Contraindications to Vaccination in the Russian Federation|journal=The Journal of Infectious Diseases|volume=181|pages=S228–31|year=2000|last1=Tatochenko|first1=Vladimir|last2=Mitjushin|first2=I. L.|doi-access=free}}

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.{{Cite web | url=http://ac360.blogs.cnn.com/2010/05/10/video-diphtheria-epidemic-threatens-haiti/ | title=CNN's Anderson Cooper talks with Sean Penn and Dr. Sanjay Gupta about the threat of diphtheria in Haiti | date=10 May 2010 | work=CNN. | url-status=dead | archive-url=https://web.archive.org/web/20161220045251/http://ac360.blogs.cnn.com/2010/05/10/video-diphtheria-epidemic-threatens-haiti/ | archive-date=20 December 2016 | df=dmy-all }}

In 2013, three children died of diphtheria in Hyderabad, India.{{Cite news | url=http://www.thehindu.com/news/cities/Hyderabad/three-kids-die-of-diphtheria/article5065637.ece?homepage=true | title=Three kids die of diphtheria | date=28 August 2013 | work=The Hindu | url-status=live | archive-url=https://web.archive.org/web/20161220221203/http://www.thehindu.com/news/cities/Hyderabad/three-kids-die-of-diphtheria/article5065637.ece?homepage=true | archive-date=20 December 2016 | df=dmy-all }}

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.{{Cite web|title = Parents of diphtheria-stricken boy feel "tricked" by anti-vaccination groups|url = http://elpais.com/elpais/2015/06/05/inenglish/1433512717_575817.html|work = El Pais|date = 5 June 2015|url-status = live|archive-url = https://web.archive.org/web/20150607000140/http://elpais.com/elpais/2015/06/05/inenglish/1433512717_575817.html|archive-date = 7 June 2015|df = dmy-all}} It was the first case of diphtheria in the country since 1986, as reported by the Spanish daily newspaper El Mundo,{{Cite web|title = Primer caso de difteria en España en casi 30 años|url = http://www.elmundo.es/salud/2015/06/02/556dbc3d268e3e16598b4589.html|work = El Mundo|date = 2 June 2015|url-status = live|archive-url = https://web.archive.org/web/20150602181425/http://www.elmundo.es/salud/2015/06/02/556dbc3d268e3e16598b4589.html|archive-date = 2 June 2015|df = dmy-all}} or from 1998, as reported by the WHO.{{Cite web|title = WHO – Diphtheria reported cases|url = http://apps.who.int/immunization_monitoring/globalsummary/timeseries/tsincidencediphtheria.html|access-date = 11 June 2015|url-status = live|archive-url = https://web.archive.org/web/20150612235540/http://apps.who.int/immunization_monitoring/globalsummary/timeseries/tsincidencediphtheria.html|archive-date = 12 June 2015|df = dmy-all}}

In March 2016, a three-year-old girl died of diphtheria in the University Hospital of Antwerp, Belgium.{{Cite web|url=http://www.standaard.be/cnt/dmf20160317_02188083|title=Meisje (3) overlijdt aan difterie in ziekenhuis|website=De Standaard|date=17 March 2016|url-status=live|archive-url=https://web.archive.org/web/20160319045227/http://www.standaard.be/cnt/dmf20160317_02188083|archive-date=19 March 2016}}

In June 2016, a three-year-old, five-year-old, and seven-year-old girl died of diphtheria in Kedah, Malacca, and Sabah, Malaysia.{{Cite web|url=http://www.thestar.com.my/news/nation/2016/06/21/story/|title=Malacca Health Dept works to contain diptheria after seven-year-old dies|date=21 June 2016|author=Murali, R.S.N.|work=thestar.com.my|url-status=live|archive-url=https://web.archive.org/web/20160624034554/http://www.thestar.com.my/news/nation/2016/06/21/story/|archive-date=24 June 2016}}

In January 2017, more than 300 cases were recorded in Venezuela.{{Cite news|url=https://www.reuters.com/article/us-venezuela-health-idUSKBN185260|title=Infant mortality and malaria soar in Venezuela, according to government data|date=9 May 2017|work=Reuters|access-date=3 June 2017|url-status=live|archive-url=https://web.archive.org/web/20170524223813/http://www.reuters.com/article/us-venezuela-health-idUSKBN185260|archive-date=24 May 2017}}{{Cite web|url=http://www.healthmap.org/site/diseasedaily/article/diphtheria-reemerges-venezuela-remains-brink-economic-collapse-22117|title=Diphtheria Reemerges as Venezuela Remains on the Brink of Economic Collapse {{!}} HealthMap|website=www.healthmap.org|access-date=3 June 2017|url-status=live|archive-url=https://web.archive.org/web/20170712034357/http://www.healthmap.org/site/diseasedaily/article/diphtheria-reemerges-venezuela-remains-brink-economic-collapse-22117|archive-date=12 July 2017}}

In 2017, outbreaks occurred in a Rohingya refugee camp in Bangladesh, and amongst children unvaccinated due to the Yemeni Civil War.[https://www.npr.org/sections/goatsandsoda/2017/12/08/569462246/diphtheria-why-is-it-back-and-what-exactly-is-it 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.{{Cite news|url=https://news.detik.com/berita/d-3774591/idi-38-anak-meninggal-karena-difteri|title=IDI: 38 Anak Meninggal karena Difteri|last=Nugraha|first=Indra Komara|work=detiknews|access-date=18 December 2017}}

In November 2019, two cases of diphtheria occurred in the Lothian area of Scotland.{{Cite news|url=https://www.bbc.co.uk/news/uk-scotland-edinburgh-east-fife-50358872|title=Two cases of deadly diphtheria detected in Lothian area|date=9 November 2019|author=BBC|work=BBC News}} Additionally, in November 2019, an unvaccinated 8-year-old boy died of diphtheria in Athens, Greece.{{Cite web|url=https://www.amea-care.gr/%ce%bf%ce%ba%cf%84%ce%ac%cf%87%cf%81%ce%bf%ce%bd%ce%bf%cf%82-%cf%80%ce%ad%ce%b8%ce%b1%ce%bd%ce%b5-%ce%b1%cf%80%cf%8c-%ce%b4%ce%b9%cf%86%ce%b8%ce%b5%cf%81%ce%af%cf%84%ce%b9%ce%b4%ce%b1-%cf%83%cf%84/|title=Οκτάχρονος πέθανε από διφθερίτιδα στην Αθήνα - Δεν είχε εμβολιαστεί|date=2019-11-28|website=ΑμεΑ Care|language=el|access-date=2019-11-28}}

In July 2022, two cases of diphtheria occurred in northern New South Wales, Australia.{{Cite news|url=https://www.theguardian.com/australia-news/2022/jul/03/toddler-diagnosed-with-first-case-of-diphtheria-of-the-throat-in-nsw-in-a-century|title=Two children diagnosed with first cases of diphtheria of the throat in NSW this century|access-date=21 July 2022}}

In October 2022, there was an outbreak of diphtheria at the former Manston airfield, 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.{{Cite web |last=Taylor |first=Diane |date=20 October 2022 |title=Diphtheria outbreak confirmed at asylum seeker centre in Kent |url=https://www.theguardian.com/science/2022/oct/20/diphtheria-outbreak-confirmed-at-asylum-seeker-centre-in-kent |archive-url=https://web.archive.org/web/20221020114017/https://www.theguardian.com/science/2022/oct/20/diphtheria-outbreak-confirmed-at-asylum-seeker-centre-in-kent |archive-date=20 October 2022 |access-date=21 October 2022 |website=The Guardian |language=en}}

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."{{cite web |url=https://www.manchestereveningnews.co.uk/news/health/ukhsa-issues-statement-case-rare-28285751 |title=UKHSA issues statement as case of rare infectious disease confirmed at UK primary school |website=The Manchester Evening News |language=en |date=13 December 2023 |access-date=14 December 2023}}

{{Reflist}}

• Hammonds, Evelynn Maxine.  Childhood's Deadly Scourge: The Campaign to Control Diphtheria in New York City, 1880-1930 (1999)
• Hammonds, Evelynn Maxine.   "The search for perfect control: A social history of diphtheria, 1880-1930" (PhD dissertation, Harvard University; ProQuest Dissertations & Theses,  1993. 9318671).

• {{cite book |last=Holmes |first=R .K. |chapter=Diphtheria and other corynebacterial infections |editor1-last=Kasper |title=Harrison's Principles of Internal Medicine |edition=16th |location=New York |publisher=McGraw-Hill |isbn=978-0-07-139140-5 |year=2005 |display-editors=etal}}
• "Antitoxin dars 1735 and 1740." The William and Mary Quarterly, 3rd Ser., Vol 6, No 2. p. 338.
• {{cite journal |last=Shulman |first=S. T. |title=The History of Pediatric Infectious Diseases |journal=Pediatric Research |volume=55 |issue=1 |year=2004 |pages=163–176 |pmid=14605240 |doi=10.1203/01.PDR.0000101756.93542.09 |pmc=7086672 }}

{{Commons}}

• {{cite web | url = https://medlineplus.gov/diphtheria.html | publisher = U.S. National Library of Medicine | work = MedlinePlus | title = Diphtheria }}
• [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30226-0/fulltext Mapping diphtheria-pertussis-tetanus vaccine coverage in Africa, 2000–2016: a spatial and temporal modelling study]

{{Medical condition classification and resources

| DiseasesDB = 3122

| ICD11 = {{ICD11|1C17}}

| ICD10 = {{ICD10|A|36||a|36}}

| ICD9 = {{ICD9|032}}

| ICDO =

| OMIM =

| MedlinePlus = 001608

| eMedicineSubj = emerg

| eMedicineTopic = 138

| eMedicine_mult = {{eMedicine2|med|459}} {{eMedicine2|oph|674}} {{eMedicine2|ped|596}}

| MeshID = D004165

}}

{{Gram-positive actinobacteria diseases}}

{{Authority control}}

Category:Bacterial diseases

Category:Wikipedia medicine articles ready to translate

Category:Wikipedia emergency medicine articles ready to translate

Category:Vaccine-preventable diseases

Category:Rare infectious diseases