Tuberculin, also known as purified protein derivative, is a combination of

proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that are used in the diagnosis of

tuberculosis Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in ...

. This use is referred to as the

tuberculin skin test The Mantoux test or Mendel–Mantoux test (also known as the Mantoux screening test, tuberculin sensitivity test, Pirquet test, or PPD test for purified protein derivative) is a tool for screening for tuberculosis (TB) and for tuberculosis diagn ...

and is recommended only for those at high risk. Reliable administration of the skin test requires large amounts of training, supervision, and practice. Injection is done into the

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...

. After 48 to 72 hours, if there is more than a five to ten millimeter area of swelling, the test is considered positive. Common side effects include redness, itchiness, and pain at the site of injection.

Allergic reactions Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...

may occasionally occur. The test may be falsely positive in those who have been previously vaccinated with BCG or have been infected by other types of

mycobacteria ''Mycobacterium'' is a genus of over 190 species in the phylum Actinomycetota, assigned its own family, Mycobacteriaceae. This genus includes pathogens known to cause serious diseases in mammals, including tuberculosis ('' M. tuberculosis'') and ...

. 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. Use is safe in

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...

. Tuberculin was discovered in 1890 by

Robert Koch Heinrich Hermann Robert Koch ( , ; 11 December 1843 – 27 May 1910) was a German physician and microbiologist. As the discoverer of the specific causative agents of deadly infectious diseases including tuberculosis, cholera (though the Vibrio ...

. Koch, best known for his work on the etiology of tuberculosis (TB), laid down various rigorous guidelines that aided the establishment between a pathogen and the specific disease that followed that were later named

Koch's postulates Koch's postulates ( )"Koch"
''

Mycobacterium tuberculosis ''Mycobacterium tuberculosis'' (M. tb) is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, ''M. tuberculosis'' has an unusual, waxy coating on its c ...

''. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...

Medical uses

The test used in the United States at present is referred to as the

Mantoux test The Mantoux test or Mendel–Mantoux test (also known as the Mantoux screening test, tuberculin sensitivity test, Pirquet test, or PPD test for purified protein derivative) is a tool for screening for tuberculosis (TB) and for tuberculosis diagn ...

. An alternative test called the

Heaf test The Heaf test, a diagnostic skin test, was long performed to determine whether or not children had been exposed to tuberculosis infection. The test was named after F. R. G. Heaf. Also known as the Sterneedle test, it was administered by a Heaf ...

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 invented by German scientist and physician

in 1890. The original tuberculin was a

glycerine Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids known ...

extract of the tubercle bacilli and was developed as a remedy for tuberculosis. This was originally considered a cure for tuberculosis, given to patients in subcutaneous doses of a brownish, transparent liquid that was gathered through cultured filtrates. However, the treatment did not result in the anticipated reduction of deaths. When the tuberculin treatment was first given to patients in 1890, a febrile reaction that lasted between four and five hours was recorded in most patients. The symptoms of these reactions included a fever that was accompanied by vomiting, rigors, or other forms of constitutional symptoms. After these symptoms became recurring in patients, Koch had noted how increasing dosages of the treatment over time resulted in quicker and more effective healing in the mild cases of tuberculosis, along with the more serious cases where progression was slower, yet still progressive. 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 patients with TB. As an example, Dr Hilda Clark's dispensary at Street, Somerset was especially noted for its efficacious treatment of the less severe cases.

Clemens von Pirquet Clemens Peter Freiherr von Pirquet (12 May 187428 February 1929) was an Austrian scientist and pediatrician best known for his contributions to the fields of bacteriology and immunology. Career Born in Vienna, he studied theology at the Universit ...

, an Austrian physician, discovered that patients who had previously received injections of horse serum or

smallpox vaccine The smallpox vaccine is the first vaccine to be developed against a contagious disease. In 1796, British physician Edward Jenner demonstrated that an infection with the relatively mild cowpox virus conferred immunity against the deadly smallpox ...

had quicker, more severe reactions to a second injection, and he coined the word ''

allergy Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...

'' 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 sparked hope for a cure. Until that time, the only effective remedy for an infectious disease was

quinine Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to ''Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg cr ...

, which was used to treat malaria. At the Tenth

International Medical Congress The International Medical Congress (french: Congrès International de Médecine) was a series of international scientific conferences on medicine that took place, periodically, from 1867 until 1913. The idea of such a congress came in 1865, dur ...

held in 1890 in Berlin, Koch unexpectedly introduced a cure for tuberculosis, which he called tuberculin. He did not reveal its composition, which was not unusual as it was not then customary to patent medicine,

Phenazone Phenazone (INN and BAN; also known as phenazon, antipyrine (USAN), or analgesine) is an analgesic (pain reducing), antipyretic (fever reducing) and anti-inflammatory drug. While it predates the term, it is often classified as a nonsteroidal anti- ...

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 Order of the Red Eagle (german: Roter Adlerorden) was an order of chivalry of the Kingdom of Prussia. It was awarded to both military personnel and civilians, to recognize valor in combat, excellence in military leadership, long and faithful se ...

. The

social hygienist The social hygiene movement was an attempt by Progressive era reformers to control venereal disease, regulate prostitution and vice, and disseminate sexual education through the use of scientific research methods and modern media techniques. Soci ...

Alfred Grotjahn Alfred Grotjahn (25 November 1869 – 4 September 1931) was a German German(s) may refer to: * Germany (of or related to) **Germania (historical use) * Germans, citizens of Germany, people of German ancestry, or native speakers of the German la ...

described the arrival of tuberculin in

Greifswald Greifswald (), officially the University and Hanseatic City of Greifswald (german: Universitäts- und Hansestadt Greifswald, Low German: ''Griepswoold'') is the fourth-largest city in the German state of Mecklenburg-Western Pomerania after Rostoc ...

: "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!" 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 Marks may refer to: Business * Mark's, a Canadian retail chain * Marks & Spencer, a British retail chain * Collective trade marks, trademarks owned by an organisation for the benefit of its members * Marks & Co, the inspiration for the novel ...

. Koch also hinted that he had received offers from the US. 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. 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. 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".

Ineffectiveness as a cure

In February 1891, a medical trial was performed on 1769 patients to whom tuberculin was administered, and the results made clear that it was not a true cure. Tuberculin failed to provide any form of protective action as only 1% of people in the trial were cured, 34% of people showed only a slight amount of improvement, 55% of the patients showed little to no change in their health, and 4% died due to the treatment having no effect. 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 on seriously ill patients. After performing autopsies on the corpses,

Rudolf Virchow Rudolf Ludwig Carl Virchow (; or ; 13 October 18215 September 1902) was a German physician, anthropologist, pathologist, prehistorian, biologist, writer, editor, and politician. He is known as "the father of modern pathology" and as the founder ...

proved that not only did tuberculin not kill the bacteria, it even activated latent bacteria. 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. Before tuberculin was released to the public, Koch had initially tested the treatment on himself to determine its toxicity to the human body, which is no longer considered a reliable or acceptable method for establishing drug safety. 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 ineffective 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. 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 Emil von Behring (; Emil Adolf von Behring), born Emil Adolf Behring (15 March 1854 – 31 March 1917), was a German physiologist who received the 1901 Nobel Prize in Physiology or Medicine, the first one awarded in that field, for his discovery ...

's introduction of his

diphtheria Diphtheria is an infection caused by the bacterium '' Corynebacterium diphtheriae''. Most infections are asymptomatic or have a mild clinical course, but in some outbreaks more than 10% of those diagnosed with the disease may die. Signs and s ...

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.

Paul Ehrlich Paul Ehrlich (; 14 March 1854 – 20 August 1915) was a Nobel Prize-winning German physician and scientist who worked in the fields of hematology, immunology, and antimicrobial chemotherapy. Among his foremost achievements were finding a cure ...

also proceeded with conspicuous caution in 1909 when introducing the first synthetically produced chemotherapeutic agent,

Salvarsan Arsphenamine, also known as Salvarsan or compound 606, is a drug that was introduced at the beginning of the 1910s as the first effective treatment for syphilis, relapsing fever, and African trypanosomiasis. This organoarsenic compound was the fi ...

, as a cure for an infectious disease,

syphilis Syphilis () is a sexually transmitted infection caused by the bacterium ''Treponema pallidum'' subspecies ''pallidum''. The signs and symptoms of syphilis vary depending in which of the four stages it presents (primary, secondary, latent, an ...

. 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 Hoechst AG () was a German chemicals then life-sciences company that became Aventis Deutschland after its merger with France's Rhône-Poulenc S.A. in 1999. With the new company's 2004 merger with Sanofi-Synthélabo, it became a subsidiary of the ...

) 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.Ernst Bäumler: Farben, Formeln, Forscher. Hoechst und die Geschichte der industriellen Chemie in Deutschland. Piper, München und Zürich 1989, p. 67. When Koch first discovered and released the testing process for tuberculosis, there was no realization of how widely this type of diagnostic test would be used. With the various clinical trials and observations made through the differing responses to tuberculin in patients with and without tuberculosis, new methods that corresponded to the backbone of this treatment began to arise. The continued use of new methods that further eliminated systemic symptoms that were caused by a local reaction at the injection site allowed for other medical advances. These included the Pirquet cutaneous test, the Moro percutaneous path test, the Mantoux intracutaneous test, and the Calmette conjunctival test. With experience gained from the

during the greater part of the last century, the current body of medical knowledge and advances were made possible by Robert Koch. Through the failures and successes of tuberculin, more than ever before is known about the causes and symptoms of tuberculosis and the measures to prevent it. In addition, the discovery of the tuberculin skin test paved the way to the world's understanding of many other mycobacterial infections as well as certain fungal infections. Coupled with that, there has been more profound research and discoveries on the immune systems of humans and animals as the idea of skin testing broadened. The in-depth understanding of diagnostic tests was not present until the tuberculin skin test was discovered.

References

External links

Tuberculin Skin Tests
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