Tuberculin - WikiHQ

Tuberculin, known in its modern form as purified protein derivative (PPD), is a combination of proteins that are used in the diagnosis of tuberculosis by injection into the skin.

Common side effects include redness, itchiness (pruritus), and pain at the site of injection. Koch, best known for his work on the etiology (cause, origin) 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. Although he initially believed it would cure tuberculosis, this was later disproved.

PPD is on the World Health Organization's List of Essential Medicines.

Medical uses

Tuberculin/PPD is injected into the skin for the tuberculin skin test. After some time the amount of swelling is measured to determine the immune system's current level of activity against tuberculosis. A high level of swelling is considered proof for tuberculosis infection. The currently globally accepted method is the Mantoux test, named after French physician Charles Mantoux who pioneered using such a test in 1907. However, this test was not reliable enough until the replacement of crude tuberculin by PPD in the 1940s. The test may be falsely positive in those who have been previously vaccinated with BCG or have been infected by other types of mycobacteria. It has comparable results if "doubtful" indications are treated as positive. The US CDC and the American Thoracic Society believe that it is less reliable because the amount of tuberculin that enters the skin cannot be accurately determined, despite the aforementioned results.

The Heaf test, a test similar to the tine test formerly used in the United Kingdom. A spring-loaded instrument with six needles is used. It stopped being used in 2005 as the manufacturer deemed the production of this instrument financially unsustainable.

Standardization

Purified protein derivative (PPD) tuberculin is a precipitate of non-species-specific molecules obtained from filtrates of sterilized, concentrated cultures. A number of "standards" were established to compare the potency of different batches of PPD, so they can be measured in a unit of activity called the international unit (IU) or tuberculin unit (TU). The IU is defined by a bioassay: the same number of international units should produce the same degree of reaction when used on similar animals. Because PPD is mostly used for the Mantoux test, this use is defined as intradermal injection, and its reaction the size of swelling.

The first (and current) international standard for PPD of human tuberculin was a batch created in 1939, called PPD-S. Each IU or TU is equivalent to 0.02 μg of the proteins in PPD. There has a constant fear of PPD-S stocks eventually running out, so many alternative standards have been made and calibrated against the PPD-S, including PPD-S2 (current US standard), RT 23 (current WHO recommendation for skin test), etc.

PPD consists of hundreds of different proteins from the tuberculosis bacterium and the bioassay method does not cover all the differences between batches. Products calibrated to the same "strength" on the same standard can still show slight differences in how they produce reactions in people receiving the test. However, the treatment did not result in the anticipated reduction of deaths.

When the tuberculin treatment was first given to patients in 1891, 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. As an example, Dr Hilda Clark's dispensary at Street, Somerset was especially noted for its efficacious treatment of the less severe cases.

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 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. 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.

Testing agent

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.

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. 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.