Tuberculin

Tuberculin, also known as purified protein derivative, is a combination of proteins that are used in the diagnosis of tuberculosis.[1] This use is referred to as the tuberculin skin test and is recommended only for those at high risk.[2] Injection is done into the skin.[2] After 48 to 72 hours if there is more than a five to ten millimeter area of swelling the test is considered positive.[2]

This article is about the antigen. For information about the tuberculin skin test, see Mantoux test.
Tuberculin
Clinical data
Trade namesAplisol, Mantoux, PPD, others
AHFS/Drugs.comMonograph
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    administration    		intradermal
    ATC code
    Legal status
    Legal status
    Identifiers
    ChemSpider
    • none

    Common side effects include redness, itchiness, and pain at the site of injection.[1] Allergic reactions may occasionally occur.[1] The test may be falsely positive in those who have been previously vaccinated with BCG or have been infected by other types of mycobacteria.[2] The test may be falsely negative within ten weeks of infection, in those less than six months old, and in those who have been infected for many years.[2] Use is safe in pregnancy.[2]

    Tuberculin was discovered in 1890 by Robert Koch.[3] Although he initially believed it would cure tuberculosis, this was later disproved.[3] Tuberculin is made out of an extract of Mycobacterium tuberculosis.[1]

    It is on the World Health Organization's List of Essential Medicines.[4]

    Medical uses

    The test used in the United States at present is referred to as the Mantoux test. An alternative test called the Heaf test was used in the United Kingdom until 2005, although the UK now uses the Mantoux test in line with the rest of the world. Both of these tests use the tuberculin derivative PPD (purified protein derivative).

    History

    Hope for a cure

    Tuberculin was discovered by German scientist and physician Robert Koch in 1890. The original tuberculin discovered by Koch was a glycerine extract of the tubercle bacilli and was developed as a remedy for tuberculosis. However, the treatment did not result in the anticipated reduction of deaths.

    British efforts to set up "dispensaries" for the examination, diagnosis and treatment of poor citizens achieved better results, as the protocol of the Edinburgh System encompassed treatment of the homes and all contacts of the TB sufferers.[5] As an example, Dr Hilda Clark's dispensary at Street, Somerset was especially noted for its efficacious treatment of the less severe cases.[6]

    Clemens von Pirquet, an Austrian physician, discovered that patients who had previously received injections of horse serum or smallpox vaccine had quicker, more severe reactions to a second injection, and he coined the word allergy to describe this hypersensitivity reaction. Soon after, he discovered that the same type of reaction took place in those infected with tuberculosis. His observations led to the development of the tuberculin skin test. Individuals with active tuberculosis were usually tuberculin positive, but many of those with disseminated and rapidly progressive disease were negative. This led to the widespread, but erroneous belief, that tuberculin reactivity is an indicator of immunity to tuberculosis.

    Effectiveness proclaimed

    In Koch's time, close to one in seven Germans died of tuberculosis. For that reason, the public reacted euphorically to the discovery of the pathogen since it aroused hopes for a cure. Until that time, the only effective remedy for an infectious disease was quinine, which was used to treat malaria.

    At the Tenth International Medical Congress held in 1890 in Berlin, Koch unexpectedly introduced a cure for tuberculosis, which he called tuberculin. He did not reveal its composition, which is understandable as it was not then customary to patent medicine, Phenazone being the only exception. The public trusted the famous physician and reacted enthusiastically. Koch was awarded the Grand Cross of the Order of the Red Eagle.

    The social hygienist Alfred Grotjahn described the arrival of tuberculin in Greifswald: “Finally the great day also arrived for Greifswald on which the Clinic for Internal Medicine was to carry out the first inoculations with tuberculin. It was celebrated like the laying of a foundation stone or the unveiling of a monument. Doctors, nurses and patients dressed in snowy white and the director, garbed in a black frock coat, stood out against a background of laurel trees: ceremonial address by the internist, execution of the vaccination on selected patients, a thunderous cheer for Robert Koch!“[7]

    Koch attempted to profit from his discovery, which was held against him since he had conducted his research at a public institution using public money. He demanded that the Ministry of Culture finance an institute to be used exclusively for tuberculin production, and estimated the annual profit at 4.5 million marks. Koch also hinted that he had received offers from the USA.[8]

    At the time, regulations for testing medicines did not yet exist. According to Koch, he had tested tuberculin on animals, but he was unable to produce the guinea pigs which had, allegedly, been cured.[9] He seemed unconcerned by the evidence that humans had a more dramatic reaction to tuberculin, versus his laboratory animals, exhibiting fever, pains in their joints, and nausea.[10] In addition to other test subjects, he tested tuberculin on Hedwig Freiberg (his mistress and later wife), who was 16 years old at the time. She relates in her memoirs that Koch had told her that she could "possibly get quite sick" but that she was "not likely to die".[11]

    Ineffectiveness as a cure

    After tuberculin was on the market, articles reporting successful treatments appeared in professional publications and the public media, only to be followed by the first reports of deaths. At first, the negative reports were not viewed with alarm, as the doctors were, after all, experimenting with seriously ill patients.[12]

    After performing autopsies on the corpses, Rudolf Virchow proved that not only did tuberculin not kill the bacteria, it even activated latent bacteria.[13] When Robert Koch was forced to reveal the composition of his "secret cure", it was discovered that he himself did not precisely know what it contained. It was an extract of tuberculosis pathogens in glycerine, and the presence of the dead pathogens themselves could also be confirmed.

    Koch asked the Prussian Minister of Culture for time off and went to Egypt, which was interpreted as an attempt to escape from the German public. A heated debate took place in the Prussian parliament in May 1891. Koch remained convinced of the value of his cure. In 1897, he presented a modified form of tuberculin, which was also useless as a therapeutic agent. This presentation, and numerous other indications, suggest that he did not intend to commit a "tuberculin scam", (a common accusation), but that he had deluded himself.

    Historical perspective and legacy

    The medical historian Christoph Gradmann has reconstructed Koch's beliefs regarding the function of tuberculin: the medicine did not kill the bacteria but rather initiated a necrosis of the tubercular tissue, thus "starving" the tuberculosis pathogen.[14] This idea was then outside customary medical theories, as it remains today.

    The tuberculin scandal was understood as a cautionary tale in regards to testing medicine. Emil von Behring’s introduction of his diphtheria antitoxin in 1893 had been preceded by lengthy clinical testing, and the serum was only slowly introduced into practical use, accompanied by a critical discussion among qualified experts.[15] Paul Ehrlich also proceeded with conspicuous caution in 1909, when introducing the first synthetically produced chemotherapeutic agent, Salvarsan, as a cure for an infectious disease, syphilis.

    In 1907, Clemens von Pirquet further developed tuberculin as a testing agent for diagnosing tuberculosis, but this was his own achievement, independent of any of Robert Koch's ideas. The company Meister Lucius & Brüning AG (later Hoechst AG) in Frankfurt/Höchst purchased the large leftover stocks of tuberculin and the company later began production under the leadership of Koch's student Arnold Libbertz.[16]

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    References
    1. "Tuberculin". The American Society of Health-System Pharmacists. Archived from the original on 9 January 2017. Retrieved 8 January 2017.
    2. "Tuberculin Skin Testing". www.cdc.gov. Archived from the original on 9 January 2017. Retrieved 8 January 2017.
    3. Evans, Alfred S. (2013). Bacterial Infections of Humans: Epidemiology and Control. Springer. p. 605. ISBN 9781475711400. Archived from the original on 2017-01-09.
    4. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
    5. National Conference on the Prevention of Destitution (1911: London); London School of Hygiene and Tropical Medicine (1911). Report of the proceedings of the public health section [of the National Conference...], held at the Caxton Hall, Westminster, on May 30th and 31st, and June 1st and 2nd, 1911 [electronic resource]. London School of Hygiene & Tropical Medicine Library & Archives Service. London : P.S. King & Son.
    6. National Conference on the Prevention of Destitution (1911: London); London School of Hygiene and Tropical Medicine (1911). Report of the proceedings of the public health section [of the National Conference...], held at the Caxton Hall, Westminster, on May 30th and 31st, and June 1st and 2nd, 1911 [electronic resource]. London School of Hygiene & Tropical Medicine Library & Archives Service. London : P.S. King & Son.
    7. Alfred Grotjahn: Erlebtes und Erstrebtes, Erinnerungen eines sozialistischen Arztes. Herbig, Berlin 1932, p. 51.
    8. Manfred Vasold: Robert Koch, der Entdecker von Krankheitserregern. Spektrum der Wissenschaften Verlagsgesellschaft, Heidelberg 2002, ISBN 3-936278-21-0, p. 80.
    9. Christoph Gradmann: Laboratory Disease, Robert Koch's Medical Bacteriology. The Johns Hopkins University Press, Baltimore 2009, ISBN 978-0-8018-9313-1, p. 106.
    10. Christoph Gradmann: Laboratory Disease, Robert Koch's Medical Bacteriology. The Johns Hopkins University Press, Baltimore 2009, ISBN 978-0-8018-9313-1, p. 101.
    11. Quoted in Manfred Vasold: Robert Koch, der Entdecker von Krankheitserregern. Spektrum der Wissenschaften Verlagsgesellschaft, Heidelberg 2002, ISBN 3-936278-21-0, p. 81.
    12. Christoph Gradmann: Laboratory Disease, Robert Koch's Medical Bacteriology. The Johns Hopkins University Press, Baltimore 2009, ISBN 978-0-8018-9313-1, p. 133f.
    13. Christoph Gradmann: Laboratory Disease, Robert Koch's Medical Bacteriology. The Johns Hopkins University Press, Baltimore 2009, ISBN 978-0-8018-9313-1, p. 136.
    14. Christoph Gradmann: Laboratory Disease, Robert Koch's Medical Bacteriology. The Johns Hopkins University Press, Baltimore 2009, ISBN 978-0-8018-9313-1, p. 100f.
    15. Christoph Gradmann: Locating Therapeutic Vaccines in Nineteenth-Century History. In: Science in Context. vol. 21, no. 2, 2008, pp. 145–160, here p. 155.
    16. Ernst Bäumler: Farben, Formeln, Forscher. Hoechst und die Geschichte der industriellen Chemie in Deutschland. Piper, München und Zürich 1989, p. 67.
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