Diphtheria is aninfection caused by thebacteriumCorynebacterium diphtheriae.[2] Most infections are asymptomatic or have a mildclinical course, but in some outbreaks, the mortality rate approaches 10%.[1] Signs and symptoms may vary from mild to severe,[1] and usually start two to five days after exposure.[2] Symptoms often develop gradually, beginning with a sore throat andfever.[1] In severe cases, a grey or white patch develops in the throat,[2][1] which can block the airway, and create a barking cough similar to what is observed incroup.[1] The neck may also swell, in part due to the enlargement of thefacial lymph nodes.[2] Diphtheria can also involve the skin, eyes, or genitals, and can cause[2][1] complications, includingmyocarditis (which in itself can result in anabnormal heart rate),inflammation of nerves (which can result inparalysis),kidney problems, and bleeding problems due tolow levels of platelets.[2]
Diphtheria is usually spread between people by direct contact,through the air, or through contact withcontaminated objects.[2][5] Asymptomatic transmission and chronic infection are also possible.[2] Different strains ofC. diphtheriae are the main cause in the variability of lethality,[2] as the lethality and symptoms themselves are caused by theexotoxin produced by the bacteria.[1] Diagnosis can often be made based on the appearance of the throat with confirmation bymicrobiological culture.[1] Previous infection may not protect against reinfection.[1]
Adiphtheria vaccine is effective for prevention, and is available in a number of formulations.[2] Three or four doses, given along withtetanus vaccine andpertussis vaccine, are recommended during childhood.[2] Further doses of the diphtheria–tetanus vaccine are recommended every ten years.[2] Protection can be verified by measuring the antitoxin level in the blood.[2] Diphtheria can be prevented in those exposed, as well as treated with theantibioticserythromycin orbenzylpenicillin.[2] In severe cases atracheotomy may be needed to open the airway.[1]
In 2015, 4,500 cases were officially reported worldwide, down from nearly 100,000 in 1980.[3] About a million cases a year are believed to have occurred before the 1980s.[1] Diphtheria currently occurs most often insub-Saharan Africa,South Asia, andIndonesia.[1][6] In 2015, it resulted in 2,100 deaths, down from 8,000 deaths in 1990.[4][7] In areas where it is still common, children are most affected.[1] It is rare in thedeveloped world due to widespreadvaccination, but can re-emerge if vaccination rates decrease.[1][8] In the United States, 57 cases were reported between 1980 and 2004.[2] Death occurs in 5–10% of those diagnosed.[2] The disease was first described in the 5th century BC byHippocrates.[2] The bacterium was identified in 1882 byEdwin Klebs.[2]
Diphtheria can cause a swollen neck, sometimes referred to as abull neck.[2]A diphtheria skin lesion on the leg
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; andlymphadenopathy.[9][10] 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.[11] Symptoms can also includecardiac arrhythmias,myocarditis, andcranial andperipheral nerve palsies.[12]
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,"[13] "true croup,"[14][15] or sometimes simply as "croup."[16] Diphtheritic croup is extremely rare in countries wherediphtheria 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.[17]
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.[18] Contact with any lesions on the skin can also lead to transmission of diphtheria, but this is uncommon.[19] 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 bezoonotic, but this has yet to be confirmed.Corynebacterium ulcerans has been found in some animals, which would suggest zoonotic potential.[20]
Diphtheria toxin (DT) is produced only byC. diphtheriae infected with a certain type ofbacteriophage.[21][22]Toxinogenicity is determined by phage conversion (also calledlysogenic 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 thetox gene. Strains of corynephage are eithertox+ (e.g., corynephage β) ortox− (e.g., corynephage γ). Thetox gene becomes integrated into the bacterial genome.[23] The chromosome ofC. diphtheriae has two different but functionally equivalent bacterial attachment sites (attB) for integration of β prophage into the chromosome.
The diphtheria toxin precursor is aprotein ofmolecular weight 60 kDa. Certain proteases, such as trypsin, selectively cleave DT to generate twopeptide chains, amino-terminal fragment A (DT-A) and carboxyl-terminal fragment B (DT-B), which are held together by adisulfide bond.[23] DT-B is a recognition subunit that gains entry of DT into the host cell by binding to the EGF-like domain ofheparin-binding EGF-like growth factor on the cell surface. This signals the cell to internalize the toxin within anendosome viareceptor-mediated endocytosis. Inside the endosome, DT is split by a trypsin-likeprotease 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 thecytoplasm.[23]
Fragment A inhibits the synthesis of new proteins in the affected cell by catalyzingADP-ribosylation ofelongation factorEF-2—aprotein that is essential to the translation step of protein synthesis. This ADP-ribosylation involves the transfer of anADP-ribose fromNAD+ to adiphthamide (a modifiedhistidine) residue within the EF-2 protein. Since EF-2 is needed for the moving oftRNA from the A-site to the P-site of theribosome during protein translation, ADP-ribosylation of EF-2 prevents protein synthesis.[24]
ADP-ribosylation of EF-2 is reversed by giving high doses ofnicotinamide (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.[25]
An adherent, dense, grey pseudomembrane covering the posterior aspect of the pharynx; in severe cases, it can extend to cover the entire tracheobronchial tree.
Diphtheria prevention poster from the UK (around 1939-1945).
Vaccination against diphtheria is commonly done in infants, and delivered as a combination vaccine, such as aDPT vaccine (diphtheria,pertussis,tetanus).Pentavalent vaccines, which vaccinate against diphtheria and four other childhood diseases simultaneously, are frequently used in disease prevention programs indeveloping countries by organizations such asUNICEF.[26]
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 requireintubation or atracheotomy. Abnormal cardiac rhythms can occur early in the course of the illness or weeks later, and can lead toheart failure. Diphtheria can also cause paralysis in the eye, neck, throat, or respiratory muscles. Patients with severe cases are put in a hospitalintensive care unit, and given diphtheriaantitoxin (consisting ofantibodies isolated from theserum of horses that have been challenged with diphtheria toxin).[27] 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.[28]
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 eradicateC. diphtheriae, and prevent its transmission to others. The Centers for Disease Control and Prevention (CDC) recommends[29] either:
Erythromycin is given (orally or by injection) for 14 days (40 mg/kg per day with a maximum of 2g/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 userifampin orclindamycin.
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][30]
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%.[28] In 2013, it resulted in 3,300 deaths, down from 8,000 deaths in 1990.[7] Better standards of living, mass immunization, improved diagnosis, prompt treatment, and more effective health care have led to a decrease in cases worldwide.[31]
In 1613,Spain experienced an epidemic of diphtheria, referred to asEl Año de los Garrotillos (The Year of Strangulations).[31]
In 1705, theMariana Islands experienced an epidemic of diphtheria andtyphus simultaneously, reducing the population to about 5,000 people.[32]
In 1735, a diphtheria epidemic swept throughNew England.[33]
Before 1826, diphtheria was known by different names across the world. InEngland, it was known as "Boulogne sore throat," as the illness had spread fromFrance. In 1826,Pierre Bretonneau gave the disease the namediphthérite (from Greek διφθέρα,diphthera 'leather'), describing the appearance of pseudomembrane in the throat.[34][35]
In 1883,Edwin Klebs identified the bacterium causing diphtheria,[38] and named itKlebs–Loeffler bacterium. The club shape of this bacterium helped Edwin to differentiate it from other bacteria. Over time, it has been calledMicrosporon diphtheriticum,Bacillus diphtheriae, andMycobacterium diphtheriae. Current nomenclature isCorynebacterium diphtheriae.[39]
In 1885,Joseph P. O'Dwyer introduced the O'Dwyer tube for laryngeal intubation in patients with an obstructed larynx. It soon replacedtracheostomy as the emergency diphtheric intubation method.[41]
In 1888,Emile Roux andAlexandre Yersin showed that a substance produced byC. diphtheriae caused symptoms of diphtheria in animals.[42][43]
In 1890,Shibasaburō Kitasato andEmil von Behring immunized guinea pigs with heat-treated diphtheria toxin.[44] They also immunized goats and horses in the same way, and showed that an "antitoxin" made fromserum of immunized animals could cure the disease in non-immunized animals. Behring used this antitoxin (now known to consist ofantibodies that neutralize the toxin produced byC. 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.[45][27] In 1901, Von Behring won the firstNobel Prize in medicine for his work on diphtheria.[46]
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.[48]
In 1901, 10 of 11 inoculatedSt. Louis children died from contaminated diphtheria antitoxin. The horse from which the antitoxin was derived died oftetanus. This incident, coupled with a tetanus outbreak inCamden, New Jersey,[49] played an important part in initiating federal regulation of biologic products.[50]
In 1905, Franklin Royer, from Philadelphia's Municipal Hospital, published a paper urging timely treatment for diphtheria and adequate doses of antitoxin.[51] In 1906,Clemens Pirquet andBéla Schick describedserum sickness in children receiving large quantities of horse-derived antitoxin.[52]
Between 1910 and 1911, Béla Schick developed theSchick 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 theMetropolitan 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.[53]
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.[28] Children represented a large majority of these cases and fatalities. One of the most infamous outbreaks of diphtheria occurred in 1925, inNome, Alaska; the"Great Race of Mercy" to deliver diphtheria antitoxin is now celebrated by theIditarod Trail Sled Dog Race.[55]
In 1926, Alexander Thomas Glenny increased the effectiveness of diphtheriatoxoid (a modified version of the toxin used for vaccination) by treating it with aluminum salts.[56] Vaccination with toxoid was not widely used until the early 1930s.[57] In 1939, Dr.Nora Wattie, who was thePrincipal Medical Officer (Maternity and Child Welfare) of Glasgow between 1934– 1964,[58] introduced immunisation clinics acrossGlasgow, and promoted mother and child health education, resulting in virtual eradication of the infection in the city.[59]
Widespread vaccination pushed cases in the United States down from 4.4 per 100,000 inhabitants in 1932 to 2.0 in 1937. InNazi 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.[60]
Between June 1942 and February 1943, 714 cases of diphtheria were recorded atSham Shui Po Barracks, resulting in 112 deaths because theImperial Japanese Army did not release supplies of anti-diphtheria serum.[61]
In 1943, diphtheria outbreaks accompanied war and disruption inEurope. The 1 million cases in Europe resulted in 50,000 deaths.[citation needed]
During 1948 inKyoto, 68 of 606 children died after diphtheria immunization due to improper manufacture of aluminum phosphate toxoid.[62]
After the breakup of the formerSoviet 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 theCommonwealth of Independent States, and resulted in 5,000 deaths.[31] In 1994, theRussian Federation had 39,703 diphtheria cases. By contrast, in 1990, only 1,211 cases were reported.[66]
In early May 2010, a case of diphtheria was diagnosed inPort-au-Prince,Haiti, after the devastating2010 Haiti earthquake. The 15-year-old male patient died while workers searched for antitoxin.[67]
In early June 2015, a case of diphtheria was diagnosed atVall d'Hebron University Hospital inBarcelona,Spain. The six-year-old child who died of the illness had not been previously vaccinated due to parentalopposition to vaccination.[69] It was the first case of diphtheria in the country since 1986, as reported by the Spanish daily newspaperEl Mundo,[70] or from 1998, as reported by the WHO.[71]
In March 2016, a three-year-old girl died of diphtheria in the University Hospital ofAntwerp,Belgium.[72]
In June 2016, a three-year-old, five-year-old, and seven-year-old girl died of diphtheria inKedah,Malacca, andSabah,Malaysia.[73]
In January 2017, more than 300 cases were recorded inVenezuela.[74][75]
In November and December 2017, an outbreak of diphtheria occurred inIndonesia, with more than 600 cases found and 38 fatalities.[77]
In November 2019, two cases of diphtheria occurred in theLothian area ofScotland.[78] Additionally, in November 2019, an unvaccinated 8-year-old boy died of diphtheria inAthens,Greece.[79]
In October 2022, there was an outbreak of diphtheria at the formerManston airfield, a formerMinistry of Defence (MoD) site inKent,England, which had been converted to anasylum 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. TheHome Office, the government department responsible for asylum seekers, refused to confirm the number of cases.[81]
In December 2023 there was an outbreak at a school inLuton, in theUnited 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."[82]
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^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], … )
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^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.
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^Harnisch, JP; Tronca E; Nolan CM; Turck M; Holmes KK (1 July 1989). "Diphtheria among alcoholic urban adults. A decade of experience in Seattle".Annals of Internal Medicine.111 (1):71–82.doi:10.7326/0003-4819-111-1-71.PMID2472081.
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