Bacteria, Epidemiology, Infectious Diseases, Pathogen of the Month

Diphtheria, the ‘Strangling Angel’: Outbreaks, Symptoms, Vaccine, and More

Author Chandana Balasubramanian , 05-Jan-2023

Diphtheria, a highly contagious bacterial disease, was one of the deadliest childhood infections in history. It caused devastating outbreaks and had a high death toll. Because of this, it was also known as the ‘children’s plague’ and struck fear in the hearts of parents worldwide. 

 

The disease is caused by the bacteria Corynebacterium diphtheriae, and humans are the only known reservoir [1,2]. What makes the bacteria so fearsome is that it releases a toxin that creates a false membrane of dead cells in the mouth and throat. These dead cells build up and, eventually, choke the infected child to death. Making matters worse, the bacteria is incredibly infectious and spreads from person to person, usually through respiratory droplets [3,4].

 

In the past, the disease had many names, including the Strangling Angel, Syrian ulcer, membranous angina, malignant croup, and Boulogne sore throat, until it received its official name of Diphtheria in 1826 [5,6]. The case-fatality rate of the disease is between 5% and 10% [1]. Children less than five years of age are at a higher risk of developing life-threatening complications [7]. 

The discovery of a vaccine drastically reduced the incidence of bacterial infection. The diphtheria vaccine is widely available in different combinations. As a result, the disease is not the high-level threat it once was [8,4].

History

 

The first set of writings describing a diphtheria-like illness in Egypt dates back to the second millennium BC. Famous Greek writers, including Hippocrates, Aretaeus, and Aëtius, presented more details about the disease in their writings during the 5th century BC, 2nd century AD, and 6th century AD, respectively.

In 1613, Spain experienced a diphtheria epidemic so devastating that the year became known as ‘El Año de los Garotillos’ — the “Year of Strangulations.” Outbreaks continued to occur in many parts of Europe every 12 years during the 18th century, especially in southwestern Europe [9]. 

In 1683, the ‘Father of Microbiology,’ Antonie van Leeuwenhoek discovered microorganisms. He termed them ‘animalcules’ or ‘little animals’ at the time. He also fashioned the first microscope based on lens-making skill. After this pioneering work, the field of microbiology progressed considerably. Many other scientists began identifying and classifying previously unknown bacteria, viruses, and parasites, leading to a greater understanding of diseases. 

In 1826, Pierre Bretonneau, a French physician, identified the C.diphtheriae bacterium and gave it an official name, diphtérite – a Greek word for leather. The term describes the leathery coating that appears in the throat of a person infected by C.diphtheriae [6]. In 1883, the bacterium was observed for the first time in diphtheritic membranes by a German-Swiss microbiologist named Edwin Klebs. It was then cultivated for the first time by Friedrich Löffler, a German bacteriologist, a year later [1]. 

In 1888, two doctors in Paris, Roux and Alexandre Yersin isolated the toxin produced by the bacterium. They demonstrated that this toxin was responsible for the bacterial infection

Around the same time, there was a breakthrough in the fight against diphtheria. Emil von Behring, a German doctor, collaborated with a Japanese bacteriologist Kitasato Shibasaburo and discovered ‘antitoxins.’ They induced passive immunity from a disease in healthy animals by injecting them with the blood serum of an infected animal. While their first focus was tetanus, they eventually achieved stellar results against diphtheria as well. For this landmark achievement, Behring received the first-ever Nobel Prize for Physiology or Medicine in 1901 [10,28]

In 1907, Theobald Smith, an American epidemiologist, bacteriologist, pathologist, and professor, was the first to observe the immune response against diphtheria in guinea pigs that were vaccinated with diphtheria toxin and antitoxin. This combination was later used to immunize children living in big cities in Europe and the US.  

In 1926, the first alum-precipitated diphtheria toxoid was licensed in the US. This was developed by Alexander Thomas Glenny, a British immunologist. A year later, Ramon and Zoeller combined the diphtheria toxoid with the tetanus toxoid. In 1943, thanks to the groundbreaking work on pertussis (whooping cough) by Grace Eldering and Pearl Kendrick, the pertussis vaccine was added to the diphtheria-tetanus mixture to create a combined DTP (Diphtheria-Tetanus-Pertussis) vaccine [10].  

Cases gradually decreased after the World Health Organization (WHO) began the universal childhood immunization program in 1974 [11]. As the vaccination program gained momentum, the demand for DTP shots skyrocketed. In 2006, around 500 million DTP vaccine doses were produced globally, with pharmaceutical giants like Sanofi Pasteur and GSK accounting for almost 20% of the overall production [10].

In 2018, data from countries that actively participated in the immunization program showed that almost 90% of children received at least one dose of the diphtheria vaccine, and around 86% of them received three doses and at least one dose of the Measles-Containing Vaccine (MCV). Despite all the immunization efforts, only 129 of 194 member countries of WHO reached the target of vaccinating over 90% of the population [11].

Epidemiology

 

Diphtheria occurs worldwide, especially in regions where vaccination coverage is inadequate. Nowadays, it is a rare disease, so seasonal patterns are not closely observed. But, in temperate areas, it is more frequent during winter and spring seasons [1]. 

Untreated and unvaccinated children under the age of five are at a higher risk of developing fatal complications than those between the ages of five and nineteen [7].

Notable outbreaks

 

 – 1613 marked the diphtheria epidemic in Spain, termed the ‘Year of Strangulations.’ Outbreaks continued to occur in many parts of Europe every 12 years during the 18th century, especially in southwestern Europe [9].

 – During the 1920s, the US had between 100,000 and 200,000 cases (140 to 150 per 100,000 population) and 13,000 and 15,000 diphtheria-related deaths yearly. 

 – In the 1940s, once the diphtheria toxoid-containing vaccines were licensed for general use, cases gradually decreased to 15 per 100,000 population [1].   

 – In the UK, diphtheria was the second leading cause of death in children after pneumonia before a vaccine was discovered [12,13]. Around 60,000 cases were reported across the country each year during this period. But, they decreased drastically after a mass immunization program began in 1942 [12].

 – In the mid-1900s, globally, over a million cases of diphtheria were reported each year globally. 

 – In the 1970s, around 60,000 deaths occured each year [14] 

 – During the 1990s, a decade-long outbreak occurred in Eastern Europe, including the Russian Federation and former Soviet Republics. Around 157,000 people were affected, and about 5,000 lost their lives [7,15]. 

 – Southeast Asian countries have consistently reported a high incidence of diphtheria since 2000. 

    • From 2000 – 2017, 77% of global diphtheria cases were from India [16]. 
    • India, Nepal, and Indonesia account for 96% – 99% of all diphtheria cases reported in the South-East Asia region during this period [17].
    • In 2018, over 50% of the 16,648 diphtheria cases reported worldwide were from India [18].

 

 – Between 2017 to 2019, a massive diphtheria outbreak in Indonesia ravaged the entire country, affecting around 20 provinces. Indonesia has one of the highest rates of diphtheria, along with India and sub-saharan African countries. 

      • In 2017, there were about 954 cases and 44 deaths. 
      • In 2018, 29 deaths were reported, and the case incidence rose to 1.386 per 100,000 population. 
      • In 2019, the number of deaths came down to 23, and the total number of cases reported during the year stood at 530 [2].

 – From 2017 to 2019, diphtheria outbreaks affected Bangladesh as well. The country became the epicenter of one of the most significant diphtheria outbreaks of the century, with around 8640 suspected cases and 45 fatalities [7]. During this period, several outbreaks occurred in South America, including Brazil, Colombia, Dominican Republic, Haiti, and Venezuela. Venezuela, in particular, had around 1785 suspected cases and 292 deaths [19]. 

 – In 2019 alone, about 22,625 cases of diphtheria were reported globally. This number represents over 400% increase in cases compared to the 4,535 reported in 2015 [20]. 

 – In 2020, a large diphtheria outbreak in Yemen claimed 330 lives and was believed to have affected 5,701 people [21]. In the same year, Vietnam saw a peak in the number of diphtheria cases recorded. Interestingly, all the 198 cases reported during the first nine months of the year were from mountainous regions where adequate vaccination coverage was challenging [22]. 

Sadly, diphtheria outbreaks continue to occur in specific regions of the world, even today. Between February and November 2022, strains of toxigenic C. diphtheriae were isolated from 50 asylum seekers in the UK. Most were men aged between 14 and 25 years [23].

How is it spread?

 

Diphtheria is contagious and can spread from person to person through:

  • Respiratory droplets released when an infected person coughs, sneezes, or talks.
  • Touching open sores or ulcers of an infected person [3].
  • Contaminated clothes, objects, and surfaces [4].

Biology of the disease

 

C.diphtheriae is a gram-negative, rod-shaped bacterium. It is non-motile. 

Once the bacterium C. diphtheriae enters the nasopharynx (the upper part of the throat behind the nose), it releases a tissue-damaging toxin. The toxin gets absorbed into the bloodstream and travels to different body tissues. It causes inflammation and can damage the heart muscle, peripheral nerves, and kidneys. It can also gradually bring down the platelet count [1].

Symptoms

 

Symptoms appear 2 – 5 days after exposure to the infection. Diphtheria can cause respiratory illness and skin infections. Within the first few days of the bacterial infection, infected individuals develop a  grayish-white membrane of dead cells over their tonsils and throat. This layer is a characteristic symptom.

Diphtheria symptoms are:

  • Sore throat
  • Weakness
  • Fever – Usually mild
  • Swollen neck
  • Suffocation – as the pseudomembrane of dead cells begins to thicken, breathing becomes difficult and patients begin to suffocate. Some people experience this within two to three days following symptom onset [24].

 

Other complications as a result of respiratory diphtheria include:

  • Heart muscle damage
  • Nerve damage
  • Kidney failure
  • Death (one in ten with respiratory diphtheria die) [25].

 

It affects the skin by causing:

  • Open sores or ulcers [24]

Diagnosis

 

If an infected individual experiences difficulty breathing, diagnosis focuses on diagnosing and addressing these symptoms. The treatment is needed as early as possible. In other cases, laboratory testing is warranted.

  • Bacterial culture is one of the ways to detect the presence of C. diphtheriae 
  • Along with a bacteria culture, an Elek test can confirm diphtheria toxin production  

 

If the culture result is negative or if the patient is already under antibiotic treatment, the following diagnostic methods can be helpful to confirm a diphtheria infection:

  • Performing a Polymerase Chain Reaction (PCR) to trace out the diphtheria tox gene
  • Culturing C. diphtheriae from specimens collected from patient’s close contacts [1]

Treatment

 

Doctors usually start the treatment as soon as they suspect a person could be sick with diphtheria [9,25]. This is because any delay in treatment could lead to severe complications like suffocation and heart problems [26]. Around 50% of patients die without treatment, especially those with respiratory diphtheria. 

After 48 hours of treatment, patients become less infectious and can no longer spread the infection to others. But, it is essential to complete the entire course of antibiotics to eliminate bacteria.

The medical treatment usually involves:

  • Administering diphtheria antitoxins to stop the bacteria from causing further damage – mainly used for treating respiratory diphtheria
  • Antibiotics such as penicillin or erythromycin kill bacteria all over the body, including the respiratory system, skin, eyes, and blood [9,25]
  • In the case of skin-related diphtheria, wounds on the skin are regularly cleaned

 

Generally, the treatment lasts for two to three weeks. Skin ulcers take anywhere between two and three months to heal completely but might leave a scar [26].

Prevention

 

Diphtheria vaccines remain our greatest weapon against the deadly bacteria. Vaccines containing diphtheria toxoids are available in various combinations. According to the CDC (Centers for Disease Control and Prevention), these vaccines are very effective in protecting against illness. Over 95% of recipients develop the required amount of immunity after three doses [1]. 

WHO recommends that all children receive the vaccine to develop necessary immunity. Three doses of the vaccine are administered during childhood and adolescence. The organization also suggests that people who were not vaccinated in their childhood or those who have not received the required doses, complete their vaccination requirements [4]. 

Available diphtheria vaccines include: 

  • DTaP – diphtheria, tetanus, and pertussis.
  • DT – diphtheria and tetanus.
  • Td – tetanus and diphtheria.
  • Tdap – tetanus, diphtheria, and pertussis [8].

 

Usually, children:

  • Under 7 years of age receive DTaP or DT, diphtheria toxoid-containing vaccines 
  • Above 7 years should receive Td or Tdap (even if they have not taken DTaP or DT shots earlier) 
  • 10 years or older can take Tdap [1].    

 

Additionally, the CDC recommends that individuals who get in contact with infected people take antibiotics to prevent themselves from becoming sick from the bacterial infection

Other preventive measures include:

  • Keeping a watch on your health condition for seven to ten days following exposure to the infection
  • Having a diagnosis done to detect the presence of diphtheria bacteria in the body
  • Performing contact tracing to trace out those who got in contact with infected individuals – usually done by the health departments [27]
  • Taking a booster shot before traveling to places endemic to the disease – Required if the last dose of the vaccine was taken more than ten years ago [26].

The GIDEON Difference

 

GIDEON is one of the most well-known and comprehensive global databases for infectious diseases. Data is refreshed daily, and the GIDEON API allows medical professionals and researchers access to a continuous stream of data. Whether your research involves quantifying data, learning about specific microbes, or testing out differential diagnosis tools – GIDEON has you covered with a program that has met standards for accessibility excellence.

References

[1] CDC, “Pinkbook: Diphtheria,” Centers for Disease Control and Prevention, 19-Oct-2022. [Online]. Available: https://www.cdc.gov/vaccines/pubs/pinkbook/dip.html 

[2] N. Izzati, A. Andriani, and R. Robi’aqolbi, “Optimal control of diphtheria epidemic model with prevention and treatment,” J. Phys. Conf. Ser., vol. 1663, no. 1, p. 012042, 2020. 

[3] CDC, “Causes and how it spreads,” Centers for Disease Control and Prevention, 09-Sep-2022. [Online]. Available: https://www.cdc.gov/diphtheria/about/causes-transmission.html 

[4] WHO, “Diphtheria: A Comparative Study,” World Health Organization, 2017. [Online]. Available: https://www.who.int/news-room/questions-and-answers/item/diphtheria 

[5] R. Henry, “Etymologia: Diphtheria,” Emerg. Infect. Dis., vol. 19, no. 11, 2013.

[6] V. M. Pace, “What you don’t know about vaccines can hurt you,” Mo. Med., vol. 112, no. 2, pp. 106–108, 2015.

[7] S. A. Truelove et al., “Clinical and epidemiological aspects of diphtheria: A systematic review and pooled analysis,” Clin. Infect. Dis., vol. 71, no. 1, pp. 89–97, 2020.

[8] CDC, “Diphtheria vaccination,” Centers for Disease Control and Prevention, 09-Sep-2022. [Online]. Available: https://www.cdc.gov/diphtheria/vaccination.html

[9] T. S. P. Tiwari and M. Wharton, “Diphtheria Toxoid,” Riga Stradins University. [Online]. Available: https://www.bkus.lv/sites/default/files/editor/diphteria_vaccines_plotkin_7ed.pdf  

[10] M. Prygiel, E. Mosiej, P. Górska, and A. A. Zasada, “Diphtheria-tetanus-pertussis vaccine: past, current & future,” Future Microbiol., vol. 17, no. 3, pp. 185–197, 2022.

[11] M. Peck, M. Gacic-Dobo, M. S. Diallo, Y. Nedelec, S. V. Sodha, and A. S. Wallace, “Global routine vaccination coverage, 2018,” MMWR Morb. Mortal. Wkly. Rep., vol. 68, no. 42, pp. 937–942, 2019.

[12] C. M. Gower et al., “The changing epidemiology of diphtheria in the United Kingdom, 2009 to 2017,” Euro Surveill., vol. 25, no. 11, 2020.

[13] C. R. Vitek and M. Wharton, “Diphtheria in the former Soviet Union: reemergence of a pandemic disease,” Emerg. Infect. Dis., vol. 4, no. 4, pp. 539–550, 1998.

[14] L. H. Blumberg et al., “The preventable tragedy of diphtheria in the 21st century,” Int. J. Infect. Dis., vol. 71, pp. 122–123, 2018.

[15] M. R. Rahman and K. Islam, “Massive diphtheria outbreak among Rohingya refugees: lessons learnt,” J. Travel Med., vol. 26, no. 1, 2019.

[16] M. V. Murhekar et al., “Immunity against diphtheria among children aged 5-17 years in India, 2017-18: a cross-sectional, population-based serosurvey,” Lancet Infect. Dis., vol. 21, no. 6, pp. 868–875, 2021.

[17] K. E. N. Clarke, A. MacNeil, S. Hadler, C. Scott, T. S. P. Tiwari, and T. Cherian, “Global epidemiology of diphtheria, 2000-20171,” Emerg. Infect. Dis., vol. 25, no. 10, pp. 1834–1842, 2019.

[18] M. V. Murhekar, “Resurgence of diphtheria in India,” J. Infect., vol. 80, no. 2, pp. 232–254, 2020.

[19] L. M. Rivera-Santamaría, D. Hincapié-Palacio, J. Ochoa, F. Vargas-Restrepo, M. C. Ospina, and S. Buitrago-Giraldo, “Seroprevalence against diphtheria in pregnant women and newborns in Colombia: New arguments to promote maternal immunization,” Vaccines (Basel), vol. 10, no. 3, p. 458, 2022.

[20] J. Ikejezie, T. Langley, S. Lewis, D. Bisanzio, and R. Phalkey, “The epidemiology of diphtheria in Haiti, December 2014-June 2021: A spatial modeling analysis,” PLoS One, vol. 17, no. 8, p. e0273398, 2022.

[21] E. Badell et al., “Ongoing diphtheria outbreak in Yemen: a cross-sectional and genomic epidemiology study,” Lancet Microbe, vol. 2, no. 8, pp. e386–e396, 2021.

[22] H. Q. Chanh et al., “Novel clinical monitoring approaches for reemergence of diphtheria myocarditis, Vietnam,” Emerg. Infect. Dis., vol. 28, no. 2, pp. 282–290, 2022.

[23] Shennae O’Boyle, Gayatri Amirthalingam, Rebecca Cordery, Norman Fry, David Litt, Josh D’Aeth and Emma O’Brien, “Diphtheria: cases among asylum seekers in England, 2022,” Gov.uk. [Online]. Available: https://www.gov.uk/government/publications/diphtheria-cases-among-asylum-seekers-in-england-2022/diphtheria-cases-among-asylum-seekers-in-england-2022 

[24] CDC, “Signs and Symptoms,” Centers for Disease Control and Prevention, 09-Sep-2022. [Online]. Available: https://www.cdc.gov/diphtheria/about/symptoms.html 

[25] CDC, “Diagnosis, treatment, and complications,” Centers for Disease Control and Prevention, 09-Sep-2022. [Online]. Available: https://www.cdc.gov/diphtheria/about/diagnosis-treatment.html 

[26] NHS, “Diphtheria,” National Health Service, 07-Jan-2022. [Online]. Available: https://www.nhs.uk/conditions/diphtheria/ 

[27] CDC, “Preventing diphtheria,” Centers for Disease Control and Prevention, 09-Sep-2022. [Online]. Available: https://www.cdc.gov/diphtheria/about/prevention.html 

[28] S. H. E. Kaufmann, “Emil von Behring: translational medicine at the dawn of immunology,” Nat. Rev. Immunol., vol. 17, no. 6, pp. 341–343, 2017.

Author
Chandana Balasubramanian

Chandana Balasubramanian is an experienced healthcare executive who writes on the intersection of healthcare and technology. She is the President of Global Insight Advisory Network, and has a Masters degree in Biomedical Engineering from the University of Wisconsin-Madison, USA.

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